U.S. patent number 10,030,010 [Application Number 15/501,295] was granted by the patent office on 2018-07-24 for route of synthesis for the preparation of suvorexant.
This patent grant is currently assigned to Sandoz AG. The grantee listed for this patent is Sandoz AG. Invention is credited to Roland Barth, Kathrin Hoferl-Prantz, Frank Richter, Gerhard Widschwenter.
United States Patent |
10,030,010 |
Barth , et al. |
July 24, 2018 |
Route of synthesis for the preparation of suvorexant
Abstract
The present invention relates to a process for the preparation
of a compound of formula (A), Further, the present invention
relates to the respective compound (A) as such and to its use in
the preparation of antifungal agent. ##STR00001##
Inventors: |
Barth; Roland (Kundl,
AT), Hoferl-Prantz; Kathrin (Kundl, AT),
Richter; Frank (Kundl, AT), Widschwenter; Gerhard
(Kundl, AT) |
Applicant: |
Name |
City |
State |
Country |
Type |
Sandoz AG |
Basel |
N/A |
CH |
|
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Assignee: |
Sandoz AG (CH)
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Family
ID: |
51265573 |
Appl.
No.: |
15/501,295 |
Filed: |
August 4, 2015 |
PCT
Filed: |
August 04, 2015 |
PCT No.: |
PCT/EP2015/067995 |
371(c)(1),(2),(4) Date: |
February 02, 2017 |
PCT
Pub. No.: |
WO2016/020405 |
PCT
Pub. Date: |
February 11, 2016 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20170217947 A1 |
Aug 3, 2017 |
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Foreign Application Priority Data
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Aug 4, 2014 [EP] |
|
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14179727 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C
269/04 (20130101); C07D 243/08 (20130101); C07C
269/06 (20130101); C07D 403/10 (20130101); C07D
249/06 (20130101); C07D 403/06 (20130101); C07D
413/14 (20130101); C07C 269/04 (20130101); C07C
271/22 (20130101); C07C 269/06 (20130101); C07C
271/20 (20130101); C07C 269/04 (20130101); C07C
271/20 (20130101) |
Current International
Class: |
C07D
243/08 (20060101); C07D 403/10 (20060101); C07D
413/14 (20060101); C07D 249/06 (20060101) |
Field of
Search: |
;540/492,575 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2628347 |
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Jan 1978 |
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DE |
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2004024720 |
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Mar 2004 |
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WO |
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2008033764 |
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Mar 2008 |
|
WO |
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2008069997 |
|
Jun 2008 |
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WO |
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2012148553 |
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Nov 2012 |
|
WO |
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2013007371 |
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Jan 2013 |
|
WO |
|
2013169610 |
|
Nov 2013 |
|
WO |
|
Other References
International Search Report and Written Opinion for PCT/
EP2015/067995, dated Nov. 2, 2016, 14 pages. cited by applicant
.
Wuts, Peter G.M, et al., Greene's Protective Groups in Organic
Synthesis, Fourth Edition, John Wiley & Sons, Inc., 2007,
Chapter 7. cited by applicant.
|
Primary Examiner: Coleman; Brenda L
Attorney, Agent or Firm: Luedeka Neely Group, P.C.
Claims
The invention claimed is:
1. A process for the preparation of a compound of formula (A)
##STR00401## or a pharmaceutically acceptable salt or solvate
thereof, wherein R.sup.1 is selected from the group consisting of
H, PG.sup.1 and R.sup.A with R.sup.A being ##STR00402## and wherein
R.sup.2 is selected from the group consisting of H, PG.sup.2 and
R.sup.B with R.sup.B being ##STR00403## and wherein PG.sup.1 and
PG.sup.2 are, independently of each other, suitable protecting
groups, and wherein n is 0 or 1, the process comprising (a)
providing a compound of formula (II) ##STR00404## wherein R.sup.E
is selected from the group consisting of H, alkyl, aryl, alkylaryl,
heteroaryl, cycloalkyl and heterocycloalkyl, (b) reacting the
compound of formula (II) with a base and optionally reducing the
compound to give the compound of formula (A).
2. The process according to claim 1, wherein the compound of
formula (A) has the structure of formula (Ia) ##STR00405## wherein
R.sup.l and R.sup.2 are as defined in claim 1.
3. The process according to claim 1, wherein the compound of
formula (A) has the structure of formula (Ib) ##STR00406## wherein
R.sup.l and R.sup.2 are as defined in claim 1, wherein in step (b)
upon reaction with the base a compound of formula (Ia) is formed,
##STR00407## and wherein step (b) further comprises reducing the
compound of formula (Ia).
4. The process according to claim 1, wherein the compound of
formula (A) has the structure of formula (IX) ##STR00408##
5. A process for the preparation of a compound of formula (IX)
##STR00409## comprising (A) preparing a compound of formula (A)
according to the method of claim 1, wherein in case n=0, at least
one of R.sup.1 or R.sup.2 is H or a protecting group, (B)
transforming the compound of step (A) into the compound of formula
(IX).
6. The process of claim 5, wherein step (A) comprises providing a
compound of formula (Ia) by a process comprising (a) providing a
compound of formula (II) ##STR00410## wherein R.sup.E is selected
from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl,
cycloalkyl and heterocycloalkyl, wherein R.sup.1 is H and R.sup.2
is PG.sup.2, (b) reacting the compound of formula (II) with a base,
to give the compound of formula (Ia), with R.sup.1 being H and with
R.sup.2 being PG.sup.2.
7. The process of claim 5, wherein step (B) comprises (c1) removal
of the protecting group PG.sup.2, (d1) reacting the compound of
formula (Ia) with R.sup.1 and R.sup.2 being H with a compound of
formula ##STR00411## wherein E is --COOH or a reactive carboxy
group, to give a compound of formula (VIIa), in which R.sup.1 is H,
##STR00412## (e1) reducing the compound, to give a compound of
formula (VIIb), in which R.sup.1 is H ##STR00413## (f1) reacting
the compound of formula (VIIb) with a compound of formula (XII)
##STR00414## wherein X* is a leaving group.
8. The process of claim 7, wherein (e1) comprises (e1-1) optionally
preparing a salt of the compound of formula (VIIb) in which R.sup.1
is H, (e1-2) purifying the compound obtained in (e1) or (e1-1),
(e1-3) optionally transforming the crystalline salt of (e1-2) in
the free base of formula (VIIb).
9. Crystalline form (A) of the compound of formula (VIIb-H)
##STR00415## 1) having an X-ray powder diffraction pattern
comprising a peak at 2-theta angle of approximately
12.4.degree..+-.0.2.degree., or at approximately
7.7.+-.0.2.degree., 11.4.degree..+-.0.2.degree.,
12.4.degree..+-.0.2.degree., 16.2.degree..+-.0.2.degree. and
18.1.degree..+-.0.2.degree., wherein the X-ray powder diffraction
pattern is measured at a temperature in the range of from 15 to
25.degree. C. with Cu--K.alpha..sub.1,2 radiation having a
wavelength of 0.15419 nm or 2) having an X-ray powder diffraction
pattern comprising a peak at 2-theta angle of approximately
12.4.degree..+-.0.2.degree., wherein the X-ray powder diffraction
pattern is measured at a temperature in the range of from 15 to
25.degree. C. with Cu--K.alpha..sub.1,2 radiation having a
wavelength of 0.15419 nm.
10. Crystalline form (I) of a compound of formula (VIIb*-H)
##STR00416## having an X-ray powder diffraction pattern comprising
a peak at 2-theta angle of approximately
11.3.degree..+-.0.2.degree., wherein the X-ray powder diffraction
pattern is measured at a temperature in the range of from 15 to
25.degree. C. with Cu--K.alpha..sub.1,2 radiation having a
wavelength of 0.15419 nm.
11. Hydrochloride salt of the compound of formula (VIIb) or formula
(VIIb*) or (VIIb*) ##STR00417## wherein R.sup.1 is H.
12. The hydrochloride salt of claim 11, wherein the salt is a
crystalline form of the hydrochloride salt of formula (VIIb*-C1)
##STR00418## having an X-ray powder diffraction pattern comprising
a peak at 2-theta angle of approximately
15.2.degree..+-.0.2.degree., wherein the X-ray powder diffraction
pattern is measured at a temperature in the range of from 15 to
25.degree. C. with Cu--K.alpha..sub.1,2 radiation having a
wavelength of 0.15419 nm.
13. A compound of formula (IX) ##STR00419## according to claim 5,
wherein the compound contains less than 5% by weight of the
regio-isomeric side product (IX-S) as impurity ##STR00420## based
on the total weight of the compound (IX), which includes the
compound (IX-S).
14. A compound of formula (A) ##STR00421## or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.1 is selected
from the group consisting of H, PG.sup.1 and R.sup.A with R.sup.A
being ##STR00422## wherein R.sup.2 is selected from the group
consisting of H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00423## wherein PG.sup.1 and PG.sup.2 are, independently of
each other, suitable protecting groups, wherein n is 0, and wherein
in case R.sup.1 is R.sup.A, R.sup.2 is not R.sup.B or H and wherein
in case R.sup.1 is H, R.sup.2 is not R.sup.B and wherein in case
R.sup.1 is Cbz, R.sup.2 is not H or R.sup.B wherein PG.sup.1 is
selected from Boc (t-butyloxycarbonyl), Cbz (carboxybenzyl), Fmoc
(Fluorenylmcthyloxycarbonyl), benzyl, acetyl, benzoyl, trityl, PNZ
(p-nitro benzvloxycarbonyl), Alloc (allyloxycarbonyl),
Trifluoroacetate, and Phthalimide, and wherein PG.sup.2 is selected
from benzyl, Cbz (carboxybenzyl), PNZ (p-nitrobenzyloxycarbonyl),
Alloc (allyloxycarbonyl), Trifluoroacetate, and Phthalimide.
15. A compound of formula (A) ##STR00424## or pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.1 is selected
from the group consisting of H, PG.sup.1 and R.sup.A with R.sup.A
being ##STR00425## wherein R.sup.2 is selected from the group
consisting of H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00426## wherein PG.sup.1 and PG.sup.2 are, independently of
each other, suitable protecting groups, wherein n is 1, and wherein
when n=1 R.sup.1 and R.sup.2 are not both H wherein PG.sup.1 is
selected from Boc (t-butyloxycarbonyl), Cbz (carboxybenzyl), Fmoc
(Fluorenylmcthyloxycarbonyl), benzyl, acetyl, benzoyl, trityl, PNZ
(p-nitro benzvloxycarbonyl), Alloc (allyloxycarbonyl),
Trifluoroacetate, and Phthalimide, and wherein PG.sup.2 is selected
from benzyl, Cbz (carboxybenzyl), PNZ (p-nitrobenzyloxycarbonyl),
Alloc (allyloxycarbonyl), Trifluoroacetate, and Phthalimide.
16. A process for the preparation of a compound of formula (IX)
##STR00427## comprising (A) preparing a compound of formula (A)
according to the method of claim 1; and (B) transforming the
compound of step (A) into the compound of formula (IX).
Description
This application is a Section 371 national phase entry of PCT
application PCT/EP2015/067995, filed Aug. 4, 2015. This application
also claims the benefit of the earlier filing date of European
patent application 14179727.4, filed Aug. 4, 2014.
The present invention relates to a process for the preparation of a
compound of formula (A)
##STR00002## or a pharmaceutically acceptable salt or solvate
thereof, to a compound (A) as such, as well as to a compound (A)
obtained or obtainable by said process. Further, the present
invention relates to processes for the preparation of intermediate
compounds useful in the synthesis of the invention and the
intermediate compounds as such.
BACKGROUND OF THE INVENTION
Orexin is a neurotransmitter that regulates wakefulness and
appetite. Orexins are excitatory neuropeptides that have a critical
role in maintaining wakefulness. Orexin receptors are found in the
mammalian brain and may have numerous implications in pathologies
such as depression; anxiety; addictions; obsessive compulsive
disorder; affective neurosis; depressive neurosis; anxiety
neurosis; dysthymic disorder; behavior disorder; mood disorder;
sexual dysfunction; psychosexual dysfunction; sex disorder;
schizophrenia; manic depression; delirium; dementia; severe mental
retardation and dyskinesias such as Huntington's disease and
Tourette syndrome; eating disorders such as anorexia, bulimia,
cachexia, and obesity; addictive feeding behaviors; binge/purge
feeding behaviors; cardiovascular diseases; diabetes;
appetite/taste disorders; emesis, vomiting, nausea; asthma; cancer;
Parkinson's disease; Cushing's syndrome/disease; basophile adenoma;
prolactinoma; hyperprolactinemia; hypophysis tumor/adenoma;
hypothalamic diseases; inflammatory bowel disease; gastric
dyskinesia; gastric ulcers; Froehlich's syndrome; adenohypophysis
disease; hypophysis disease; adenohypophysis hypofunction;
adenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's
syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea;
hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal
dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders
of growth hormone deficiency; idiopathic growth deficiency;
dwarfism; gigantism; acromegaly; disturbed biological and circadian
rhythms; sleep disturbances associated with diseases such as
neurological disorders, neuropathic pain and restless leg syndrome;
heart and lung diseases, acute and congestive heart failure;
hypotension; hypertension; urinary retention; osteoporosis; angina
pectoris; myocardial infarction; ischemic or hemorrhagic stroke;
subarachnoid hemorrhage; ulcers; allergies; benign prostatic
hypertrophy; chronic renal failure; renal disease; impaired glucose
tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated
sensitivity to pain such as hyperalgesia, causalgia, and allodynia;
acute pain; burn pain; atypical facial pain; neuropathic pain; back
pain; complex regional pain syndrome I and II; arthritic pain;
sports injury pain; pain related to infection, e.g. HIV,
post-chemotherapy pain; post-stroke pain; post-operative pain;
neuralgia; conditions associated with visceral pain such as
irritable bowel syndrome, and angina; migraine; urinary bladder
incontinence, e.g. urge incontinence; tolerance to narcotics or
withdrawal from narcotics; sleep disorders; sleep apnea;
narcolepsy; insomnia; parasomnia; jet lag syndrome; and
neurodegenerative disorders including nosological entities such as
disinhibition-dementia-parkinsonism-amyotrophy complex;
pallido-ponto-nigral degeneration; epilepsy; seizure disorders and
other diseases related to general orexin system dysfunction.
Some orexin receptor antagonists are capable of influencing at
least some of the above described pathological conditions. In
particular, orexin receptor antagonists capable of promoting sleep
in animals and humans are described in the art. One example for
such an orexin receptor antagonist is
[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-m-
ethyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone which has the
structure according to Formula I
##STR00003## and which is, e.g., described in US 2008/0132490, WO
2008/069997 and Cox et al. (2010) Journal of Medicinal Chemistry,
53(14): 5320-5332. Alternative names for this compound are
5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-thiazol-2-yl)benzoyl]-1-
,4-diazepan-1-yl}-1,3-benzobenzoxazol and
[(R)-4-(5-chloro-benzooxazol-2-yl)-7-methyl-[1,4]diazepan-1-yl]-(5-methyl-
-2-[1,2,3]triazol-2-yl-phenyl)-methanone.
The synthesis of
[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-meth-
yl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (herein also referred
to as "Suvorexant" or "orexin receptor antagonist") is described in
WO 2008/069997. There, a synthesis that is based on a chiral
resolution by chiral HPLC (high performance liquid chromatography)
is described. The first step of this synthesis involves a
1,4-addition of Boc-ethylenediamine to methyl vinylketone followed
by a Cbz-protection of the free amine to give a Boc-protected
intermediate. The Boc-protecting group is then cleaved with HCl and
a 7-membered ring is closed by a reductive amination reaction
sequence to give a racemic compound which after re-protection of
the free amine with a Boc-protective group is resolved by
preparative chiral HPLC. The resulting enantiomerically pure amine
is then coupled with a triazole benzoic acid derivative under
standard peptide coupling conditions. Hydrogenation cleaves the
Cbz-protecting group and the resulting amine is then finally
coupled with a benzoxazole derivative to give Suvorexant. However,
in this linear sequence a large number of steps is needed to
provide Suvorexant with only rather low yields. Further, the
synthesis is disadvantageous in that a chiral resolution by
preparative HPLC is needed, a process which is costly and thus not
suitable for the preparative scale.
A further synthesis of Suvorexant is described in WO 2012/148553.
This process patent discloses a different route towards Suvorexant.
According to WO 2012/148553, chloroaminophenol is condensed with
thiophosgene to give mercaptobenzoxazole which is then converted
into a ketone by treatment with oxalyl chloride/DMF followed by a
one-pot reaction with mono Boc-protected ethylenediamine and
vinylketone. The Boc-protecting group is then cleaved to give an
intermediate which is then cyclized by a transfer hydrogenation
with a costly and very specific ruthenium catalyst to give an
enantiomerically pure compound comprising a free amine group. The
amine is then coupled with the acid chloride of a triazole benzoic
acid derivative to give Suvorexant.
A stereoselective Suvorexant synthesis includes a tandem
enantioselective transamination/ring formation and is described in
WO2013/169610. The synthesis starts with the preparation of a
mesylate under standard conditions which is then converted into an
amine in the presence of a (R)-selective sitagliptin transaminase
and the intermediately formed amine cyclizes to give the
seven-membered diazepane ring. This step requires a strict control
of process parameters to suppress the formation of an undesired
impurity (regioisomer). Further, a very specific and sensitive
enzyme needs to be employed which again renders the process
disadvantageous for the preparative scale.
Thus, there is still the need for an improved synthesis of
Suvorexant which provides Suvorexant in high yields and which
overcomes the disadvantages of the processes described in the prior
art, such as the use of costly and complex catalyst systems and
sensitive enzymes.
SUMMARY OF THE INVENTION
Surprisingly, it was found that this object can be solved by a
process for the preparation of a compound of formula (A)
##STR00004## or a pharmaceutically acceptable salt or solvate
thereof, wherein (A) is preferably (A*)
##STR00005## and wherein R.sup.1 is selected from the group
consisting of H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00006## and wherein R.sup.2 is selected from the group
consisting of H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00007## and wherein PG.sup.1 and PG.sup.2 are, independently
of each other, suitable protecting groups, and wherein n is 0 or 1,
the process comprising (a) providing a compound of formula (II)
##STR00008## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, (b) reacting the compound of
formula (II) with a base and optionally reducing the compound to
give the compound of formula (A), preferably (A*).
Further, the present invention relates to a compound of formula
(A)
##STR00009## or a pharmaceutically acceptable salt or solvate
thereof, wherein (A) is preferably
##STR00010## wherein R.sup.1 is selected from the group consisting
of H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00011## and wherein R.sup.2 is selected from the group
consisting of H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00012## and wherein PG.sup.1 and PG.sup.2 are, independently
of each other, suitable protecting groups, and wherein n is 0 or 1,
and wherein in case n=0 and R.sup.1 is R.sup.A, R.sup.2 is not
R.sup.B or H or, wherein in case n=0 and R.sup.1 is R.sup.A,
R.sup.B is PG.sup.1 and wherein in case n=0 and R.sup.1 is H,
R.sup.2 is not R.sup.B or, wherein in case n=0 and R.sup.1 is H,
R.sup.2 is H or PG.sup.2 and wherein in case n=0 and R.sup.1 is Cbz
R.sup.2 is not H or Boc or R.sup.B and wherein when n=1 R.sup.1 and
R.sup.2 are not both H.
Further, the present invention also relates to a compound (IX)
##STR00013## obtained or obtainable by the above described method,
wherein the compound comprises less than 5% by weight, more
preferably less than 2% by weight, more preferably less than 1% by
weight, more preferably less than 100 ppm, of the regio-isomeric
side product (IX-S) as impurity
##STR00014## based on the total weight of the compound (IX), which
includes the compound (IX-S). Preferably, the compound (IX) does
not comprise the region-isomeric compound (IX-S) as impurity.
Further, the present invention relates to the use of a compound of
formula (A), or (A*), as described above, for the preparation of a
compound of formula (IX)
##STR00015##
Further, the present invention relates to crystalline compound of
formula (VIIb-H), preferably of formula (VIIb*-H) and salts,
preferably crystalline salt thereof.
Further, the present invention relates to crystalline form (A) of
compound (VIIb-H), to crystalline form (I) of compound (VIIb*-H),
to crystalline form (I-S) of the sulphate salt of compound
(VIIb*-H) and to crystalline form (I-Cl) of the hydrochloride salt
of compound (VIIb*-H), all as disclosed herein below.
DETAILED DESCRIPTION
The process for the preparation of a compound of formula (A)
##STR00016## or a pharmaceutically acceptable salt or solvate
thereof, wherein (A) is preferably (A*)
##STR00017## and wherein R.sup.1 is selected from the group
consisting of H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00018## and wherein R.sup.2 is selected from the group
consisting of H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00019## and wherein PG.sup.1 and PG.sup.2 are, independently
of each other, suitable protecting groups, and wherein n is 0 or 1,
comprises (a) providing a compound of formula (II)
##STR00020## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, (b) reacting the compound of
formula (II) with a base and optionally reducing the compound to
give the compound of formula (A), preferably (A*). The Compound
A
As described above, the compound of formula (A) has the
structure
##STR00021## wherein n is 1 or 0. Thus the compound (A) has, e.g.,
the structure (Ia) or (Ib)
##STR00022##
Thus, the present invention also relates to a method, as described
above, and to a compound obtained or obtainable by said method,
wherein the compound (A) has the structure
##STR00023## Residue R.sup.1:
As described above, R.sup.1 is selected from the group consisting
of H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00024## wherein PG.sup.1 is a suitable protecting group.
Thus, the compound of formula (A) has, e.g., a structure selected
from the group consisting of
##STR00025## i.e. a structure selected from the group consisting
of
##STR00026##
The term "suitable protecting group" as used herein is denoted to
encompass any amino protecting group. The term "protecting group"
as such refers to a chemical moiety that can be selectively
attached to and removed from a particular chemically reactive
functional group in a molecule to prevent it from participating in
undesired chemical reactions. The protecting group will vary
depending on reaction conditions to be employed and the presence of
additional reactive or protecting groups in the molecule. It is
understood that the term "amino protecting group" is a chemical
moiety being attached to a former amino group. After removal of the
protecting group, the free amine is regained. Representative
protecting groups for amino groups are well known to those skilled
in the art and are described, for example, in T. W. Greene and G.
M. Wuts, Protecting Groups in Organic Synthesis, Third Edition,
Wiley, N.Y., 1999, and references cited therein.
An "amino-protecting group" preferably includes both acyclic as
well as cyclic protecting groups. A "cyclic protecting group" is a
group which, together with the N to which it is bound, forms a
cyclic group. Preferred protecting groups for PG.sup.1 include, but
are not limited to, carbamates, such as Boc (t-butyloxycarbonyl,
Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc
(allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl,
benzylidene, tosyl, PNZ, trifluoroacetate, phtalimide and the like;
cyclic imide derivatives, such as succinimide and phthalimide;
amides, such as formyl, (un)substituted acetyl, and benzoyl; and
trialkyl silyl groups, such as t-butyldimethylsilyl and
triisopropylsilyl. Particularly preferred amino-protecting groups
include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl, Cbz, PNZ,
Alloc, Trifluoroacetate, Phthalimide and the like. Most preferably,
PG.sup.1 is wherein PG.sup.2 is selected from the group consisting
of Benzyl, t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc,
Trifluoroacetate and Phthalimide, more preferably PG.sup.1 is a Boc
group or a Cbz group, more preferably Boc.
Thus, compound A is preferably selected from the group consisting
of
##STR00027##
Preferably R.sup.1 is selected from the group consisting of H,
##STR00028## Most preferably R.sup.1 is H. Residue R.sup.2:
As descried above, R.sup.2 is selected from the group consisting of
H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00029## and wherein PG.sup.2 is a suitable protecting group,
and wherein n is 0 or 1.
Thus, the compound of formula (A) has, e.g., a structure selected
from the group consisting of
##STR00030## i.e. a structure selected from the group consisting
of
##STR00031##
PG.sup.2 is a suitable protecting group as defined above in
connection with PG.sup.1. Preferred protecting groups for PG.sup.2
include, but are not limited to, carbamates, such as Boc
(t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc
(fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and
ethyl carbamates; trityl, benzyl, benzylidene, tosyl, PNZ,
trifluoroacetate, phtalimideand the like; cyclic imide derivatives,
such as succinimide and phthalimide; amides, such as formyl,
(un)substituted acetyl, and benzoyl; and trialkyl silyl groups,
such as t-butyldimethylsilyl and triisopropylsilyl. Particularly
preferred amino-protecting groups include Boc, Cbz, Fmoc, benzyl,
acetyl, benzoyl, trityl, Cbz, PNZ, Alloc, Trifluoroacetate,
Phthalimide and the like. Most preferably, PG.sup.1 is wherein
PG.sup.2 is selected from the group consisting of Benzyl,
t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc, Trifluoroacetate and
Phthalimide, more preferably PG.sup.2 is a Boc group or a Cbz
group, more preferably Cbz.
Thus, compound A is preferably selected from the group consisting
of
##STR00032##
It is to be understood that in case R.sup.1 and R.sup.2 are both
protecting groups, PG.sup.1 and PG.sup.2 preferably differ from
each other. In this case, R.sup.1 and R.sup.2 are preferably
orthogonal protecting groups.
The term "orthogonal protecting group" refers to a protecting group
that is chemically resistant under one set of selected conditions,
but is liable under another set of conditions, i.e. under certain
conditions either PG.sup.1 is cleaved and PG.sup.2 is not, or vice
versa. In such case, PG.sup.1 is preferably Boc and PG.sup.2 is
preferably Cbz.
A bond shown as "" in any one of the compounds shown above and
below is denoted to represent a single bond, wherein the resulting
structure including the bond "" encompasses the single (isolated) S
isomer or the single (isolated) R isomer as well as mixtures of the
S and R isomer.
Preferably, compound A e.g. has as structure selected from the
structure shown in the table below:
TABLE-US-00001 ##STR00033## Struc- ture Num- ber n R.sup.1 R.sup.2
1 1 H H 2 1 H Cbz 3 1 H ##STR00034## 4 1 Boc H 5 1 Boc Cbz 6 1 Boc
##STR00035## 7 1 ##STR00036## H 8 1 ##STR00037## Cbz 9 1
##STR00038## ##STR00039## 10 1 ##STR00040## H 11 1 ##STR00041## Cbz
12 1 ##STR00042## ##STR00043## 13 0 H H 14 0 H Cbz 15 0 H
##STR00044## 16 0 Boc H 17 0 Boc Cbz 19 0 Boc ##STR00045## 19 0
##STR00046## H 20 0 ##STR00047## Cbz 21 0 ##STR00048## ##STR00049##
22 0 ##STR00050## H 23 0 ##STR00051## Cbz 24 0 ##STR00052##
##STR00053##
Thus, the present invention also relates to a method for the
preparation of a compound (A), as described above, and a compound
obtained or obtainable by said process, wherein the compound has a
structure selected from any one of the structures 1 to 24 shown
above.
In particular, the present invention relates to a compound of
formula (IX) shown above (which corresponds to structure 21 shown
above), the compound being obtained or obtainable by the above
described process, wherein said compound comprises less than 5% by
weight, more preferably less than 2% by weight, more preferably
less than 1% by weight, more preferably less than 100 ppm, of the
regio-isomeric side product (IX-S) as impurity
##STR00054## based on the total weight of the compound (IX), which
includes the compound (IX-S). Preferably, the compound (IX) does
not comprise the region-isomeric compound (IX-S) as impurity.
Further, the present invention also relates to a compound of
formula (A) as such
##STR00055## or to a pharmaceutically acceptable salt or solvate
thereof, wherein (A) is preferably
##STR00056## wherein R.sup.1 is selected from the group consisting
of H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00057## and wherein R.sup.2 is selected from the group
consisting of H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00058## and wherein PG.sup.1 and PG.sup.2 are, independently
of each other, suitable protecting groups, and wherein n is 0 or 1,
and wherein in case n=0 and R.sup.1 is R.sup.A, R.sup.2 is not
R.sup.B or H or, wherein in case n=0 and R.sup.1 is R.sup.A R.sup.B
is PG.sup.1 and wherein in case n=0 and R.sup.1 is H, R.sup.2 is
not R.sup.B or, wherein in case n=0 and R.sup.1 is H, R.sup.2 is H
or PG.sup.2 and wherein in case n=0 and R.sup.1 is Cbz R.sup.2 is
not H or Boc or R.sup.B and wherein when n=1 R.sup.1 and R.sup.2
are not both H.
In case, R.sup.1 is R.sup.A and R.sup.2 is R.sup.B and n is 0, the
compound having the structure (IX) preferably comprises less than
5% by weight, more preferably less than 2% by weight, more
preferably less than 1% by weight, more preferably less than 100
ppm, of the regio-isomeric side product (IX-S) as impurity
##STR00059## based on the total weight of the compound (IX), which
includes the compound (IX-S). Preferably, the compound (IX) does
not comprise the region-isomeric compound (IX-S) as impurity.
Preferably, the present invention relates to any one of the
compounds 1 to 24 shown above as such. This will be outlined
hereinunder in further detail.
Step (b)
In step (b) of the process of the invention, the compound of
formula (II)
##STR00060## after is reacted with a base, and optionally
subsequently reduced, to give, optionally further steps, the
compound (A). Upon reaction with the base, the 7-membered ring of
compound (A) is formed ("cyclization reaction").
The reaction may be carried out in any suitable solvent known to
those skilled in the art. Preferably, the cyclization reaction is
carried out in an organic solvent, more preferably in a solvent
selected from the group consisting of R.sup.E--OH, tetrahydrofuran,
2-methyltetrahydrofuran, methyltertbutylether, diethylether,
diisopropylether, toluene, acetonitrile and mixtures of two or more
thereof, with R.sup.E being as described above and below,
preferably wherein R.sup.E is selected from the group consisting of
alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl.
Preferably the solvent has the structure R.sup.E--OH, with R.sup.E
being as described above and below, preferably wherein R.sup.E is
selected from the group consisting of alkyl, aryl, alkylaryl,
heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein
R.sup.E alkyl, more preferably wherein R.sup.E methyl, ethyl or
propyl, more preferably wherein R.sup.E methyl. Preferably, the
cyclization is carried out at a temperature in the range of from
-20 to 80.degree. C., more preferably in the range of from 0 to 50,
more preferably in the range of from 20 to 30.degree. C. During the
reaction, the temperature may be varied or held essentially
constant.
Preferably, as base, a base selected from the group consisting of
NaOR.sup.E, Na-tert.butoxid, K-tert.butoxid, NaNH.sub.2, DBU,
Tetramethylguanidin, Na--CH.sub.2S(O)CH.sub.3 and mixtures of two
or more thereof is employed, with R.sup.E being selected from the
group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl
and heterocycloalkyl, more preferably wherein R.sup.E alkyl, more
preferably wherein R.sup.E methyl, ethyl or propyl, more preferably
wherein R.sup.E methyl. Most preferably, the base is sodium
methanolate.
The weight ratio of base to compound of formula (II) is preferably
in the range of from 0 to 8, more preferably in the range of from 1
to 5.
Generally, when providing the reaction mixture to be reacted in
(b), the sequence of mixing the components of the reaction mixture
is not subject to specific restrictions. Preferably, the compound
of formula (II) is first admixed with at least a portion of a
suitable solvent and, to the resulting mixture, the base is added
which, for example, can be employed as mixture with at least a
portion of the solvent or as such.
Compound (II) is preferably allowed to react with the base for a
time in the range of from 0 to 24 h, more preferably in the range
of from 0 to 5 h, more preferably in the range of from 0 to 3
h.
In case compound (A) has the structure (Ia) (which means that n in
compound (A) is 1), in step (b) the compound of formula (II) is
reacted with a base to give, optionally after further steps, the
compound (A). In this case, no additionally reduction step is
necessary. Directly upon reaction with the base, the 7-membered
ring of compound (A) is formed ("cyclization reaction").
In case compound (A) has the structure (Ib) (which means that n in
compound (A) is 0), in step (b) the compound of formula (II) is
reacted with a base to give, as intermediate product, the compound
of formula (Ia), which is thereafter reduced to give, optionally
after further steps, the compound (A). In this case, a reduction of
the carbonyl group is thus carried out.
Thus, the present invention also relates to a process, as described
above, as well as to a compound obtained or obtainable by said
process, wherein the compound of formula (A) has the structure of
formula (Ib), and wherein in step (b), upon reaction with the base,
a compound of formula (Ia) is formed
##STR00061## and wherein step (b) further comprises reducing the
compound of formula (Ia).
It is to be understood that in this case compound (Ia) may be
isolated or may be directly reduced in situ to give the compound of
formula (Ib). If such isolation is carried out, this may be carried
out by any method known to those skilled in the art. Such isolation
may comprise one or more stages wherein preferably at least one
stage comprises a purification, such as an extraction and/or a
precipitation and/or filtration.
Preferably, step (b) comprises (b1) reacting the compound of
formula (II) with a base to give a composition comprising a
compound of formula (Ia)
##STR00062## (b2) optionally purifying the composition obtained in
(b1),
(b3) optionally reducing the compound of formula (Ia) to give a
compound of formula (Ib)
##STR00063##
As mentioned above with respect to step (b), also step (b1) is
preferably carried out in an organic solvent, more preferably in a
solvent selected from the group consisting of methanol, ethanol,
propanol, isopropanol, butanol, s-butanol, t-butanol,
tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether,
diethylether, diisopropylether, toluene, acetonitrile and mixtures
of two or more thereof. Preferably the solvent has the structure
R.sup.E--OH is employed, with R.sup.E being as described above and
below, preferably wherein R.sup.E is selected from the group
consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl.
Preferably, step (b1) is carried out at a temperature in the range
of from -20 to 80.degree. C., more preferably in the range of from
0 to 50, more preferably in the range of from 20 to 30.degree. C.
During the reaction, the temperature may be varied or held
essentially constant.
As to step (b3), step (b3) is carried out in an organic solvent,
more preferably in a solvent selected from the group consisting of
methanol, ethanol, nPrOH (n-propanol), i-PrOH (isopropanol), THF
(tetrahydrofuran), 2-MeTHF (2-methyl-tetrahydrofuran), MTBE
(Methyl-tert-butylether), DIPET (diisiopropylethylether), toluene,
acetonitrile, CH.sub.2Cl.sub.2 and mixtures of two or more
thereof.
Preferably, step (b3) is carried out at a temperature in the range
of from -20.degree. C. to 110.degree. C.
Preferably, in step (b3), the compound is reduced by reaction with
a reducing agent selected from the group consisting of NaBH.sub.4,
NaCNBH.sub.3, NaBH(OAc).sub.3, LiAlH.sub.4, LiBH.sub.4 and H.sub.2
in the presence of transition metals, wherein the transition metal
is preferably selected from the group consisting of IR, Pt, Fe, Rh,
Pd, Re, Ru, Ni and Co. More preferably, the reducing agent is
selected from the group consisting of NaBH.sub.4, NaCNBH.sub.3,
NaBH(OAc).sub.3, LiAlH.sub.4 and LiBH.sub.4, more preferably the
reducing agent is NaBH.sub.4, NaCNBH.sub.3 or NaBH(OAc).sub.3, more
preferably NaBH.sub.4.
Preferably, the compound (A) has the structure (Ia*) or (Ib*)
##STR00064##
Thus, in step (b), preferably compound (Ia*) or (Ib*) is prepared.
Thus, preferably, in step (b) of the process of the invention, the
compound of formula (II)
##STR00065## is reacted with a base and optionally subsequently
reduced to give, optionally after further steps, the compound (A),
with (A) being (Ia*) or (Ib*). Upon reaction with the base, the
7-membered ring of compound (A) is formed ("cyclization
reaction").
It is to be understood that since compound (II) comprises the
single bond shown as "", i.e. that compound (II) has either the
structure
##STR00066## or consists of a mixture of
##STR00067## as mentioned above.
In case compound (A) has the structure (A*), such as (Ia*) or
(Ib*), preferably in step (a) compound (II) is provided in the
correct stereochemistry, i.e. as compound (II*)
##STR00068## This compound is then employed in step (b) instead of
the racemic mixture consisting of (II*) and (II**) shown above.
According to an alternative preferred embodiment, in case compound
(II) consists of a racemic mixture, in step (b), in the cyclization
reaction of compound (II), a compound (A) consisting of a racemic
mixture is obtained. Preferably, in this case, a chiral resolution
of (A) us carried out. More preferably, in this case, R.sup.2 is H,
and compound (A) is (A1),
##STR00069## which consists of a racemic mixture of the compounds
(A1*) and (A1**) is obtained,
##STR00070## wherein the compound (A1) contains from 20 to 75% by
weight-% of the compound of formula (A1*) based on the total weight
of the sum of (A1*) and (A1**), and wherein this mixture is then
resolved by chiral resolution to finally give, optionally after
further steps, the compound (A) in which R.sup.2 is H.
Preferably, this is carried out by (I) adding a single stereoisomer
of a chiral acid and precipitating, preferably crystallizing, a
chiral acid salt (T) of compound (A1), thereby obtaining a mixture
comprising the precipitated, preferably crystallized, tartaric acid
salt (T) and the solvent, (II) preferably separating the
precipitated, preferably crystallized, chiral acid salt (T) of the
compound of formula (A1) from the mixture obtained in (I), wherein
the chiral acid salt (T) contains at least 80% by weight of the
chiral acid salt of the compound of formula (A1*) based on the
total weight of the chiral acid salt of the compound of formula
(A1), (III) converting the chiral acid salt (T) to the free
base.
Preferably, in step (I), upon addition of the chiral acid in a
suitable solvent, a chiral acid salt (T*) of at least part of the
compound of formula (II) is formed, and at least part of this
chiral acid salt (T*) formed is precipitated, preferably
crystallized, thereby obtaining a mixture comprising the
precipitated, preferably crystallized, tartaric acid salt (T) and
the solvent.
The chiral acid is preferably a single stereoisomer of a tartaric
acid derivative, more preferably of a tartaric acid derivative
selected from the group consisting of Ditoluoyl tartaric acid,
Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl
tartaric acid mono(dimethylamide) and a mixture of two or more
thereof.
The term "single stereoisomer of a chiral acid" in this context is
denoted to mean that the chiral acid comprises less than 1% by
weight, preferably less than 0.5% by weight, more preferably less
than 0.1% by weight, more preferably less than 0.05% by weight,
more preferably less than 0.01% by weight, more preferably
essentially no, more preferably no impurities of respective other
stereoisomers of the chiral acid, based on the total weight of the
chiral acid. In case the chiral acid is a tartaric acid derivative
being a mixture of two or more of 2,3-Ditoluoyl tartaric acid,
2,3-Dibenzoyl tartaric acid, 2,3-Dianisoyl tartaric acid and
2,3-Dibenzoyl tartaric acid mono(dimethylamide), respectively, this
means that of each of the chiral acid derivatives within the
mixture only a single stereoisomer is present.
Preferably, the process comprises (I) forming a chiral acid salt,
preferably a tartaric acid salt, (T*) of at least part of the
compound of formula (A1) by treating the compound of formula (A1)
with a single stereoisomer of a chiral acid, preferably of a
tartaric acid derivative selected from the group consisting of
Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl
tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a
mixture of two or more thereof, in a suitable solvent, and
precipitating, preferably crystallizing, at least part of the
tartaric acid salt (T*) formed, thereby obtaining a mixture
comprising the precipitated, preferably crystallized, tartaric acid
salt (T) and the solvent; (II) preferably separating the
precipitated, preferably crystallized, chiral acid salt (T) of the
compound of formula (A1) from the mixture obtained in (I), wherein
the chiral acid salt (T) of the compound of formula (A1) contains
at least 80% by weight of the chiral acid salt of the compound of
formula (A1*) based on the total weight of the chiral acid salt of
the compound of formula (A1), (III) converting the chiral acid salt
(T) of (A1) to the free base (A1*).
Thus, the present invention also relates to a process, as described
above, and a compound obtained or obtainable by the above described
method, the method comprising (a) providing a compound of formula
(II),
##STR00071## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, (b) reacting the compound of
formula (II) with a base and optionally reducing the compound
and/or purifying the compound, to give a compound (A1) which
consists of an enantiomeric mixture of the compounds (A1*) and
(A1**),
##STR00072## (I) forming a chiral acid salt, preferably a tartaric
acid salt, (T*) of at least part of the compound of formula (A1) by
treating the compound of formula (A1) with a single stereoisomer of
a chiral acid, preferably a single stereoisomer of a tartaric acid
derivative, more preferably of a tartaric acid derivative selected
from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl
tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid
mono(dimethylamide) and a mixture of two or more thereof, in a
suitable solvent, and precipitating, preferably crystallizing, at
least part of the tartaric acid salt (T*) formed, thereby obtaining
a mixture comprising the precipitated, preferably crystallized,
tartaric acid salt (T) and the solvent, (II) preferably separating
the precipitated, preferably crystallized, chiral acid salt (T) of
the compound of formula (A1) from the mixture obtained in (I),
wherein the chiral acid salt (T) of the compound of formula (A1)
contains at least 90% by weight of the chiral acid salt of the
compound of formula (A1*) based on the total weight of the chiral
acid salt of the compound of formula (A1), (III) converting the
chiral acid salt (T) of (A1) to the free base (A1*), wherein (A) is
(A1*). Step (I)
The compound of formula (A1) employed in (I) contains of from 20 to
75% by weight, more preferably of from 40 to 60% by weight, of the
compound of formula (A1*) based on the total weight of the sum of
(A1*) and (A1**).
In step (b), at least part of the compound of formula (A1) obtained
in the cyclization reaction is transformed into the corresponding
chiral acid salt, preferably tartaric acid salt, (T*). The chiral
acid salt (T*) contains the chiral acid salt of the compound of
formula (A1*), e.g. in an amount in the range of from 1 to 80% by
weight, such as in the range of from 10 to 70% by weight, or in the
range of from 30 to 60% by weight, or in the range of from 45 to
55% by weight, based on the total amount of the chiral acid salt
(T*).
Subsequently, at least part of (T*) is precipitated, preferably
crystallized. This is preferably achieved by contacting (treating)
the compound of formula (A1) in a suitable solvent with the chiral
acid. Thereby, a mixture comprising the crystallized chiral acid
salt (T) of the compound of formula (A1*) and the solvent is
formed. As mentioned above, the precipitated, preferably
crystallized, tartaric acid salt (T) of the compound of formula
(A1) contains at least 90% by weight of chiral acid salt of the
compound of formula (A1*) based on the total weight of the chiral
acid salt of the compound of formula (A1).
It is to be noted that the mixture obtained in step (I) may
comprise further compounds, in particular non crystalline forms of
the compound of formula (A1) and salts thereof. Preferably, the
mixture obtained in (I) comprises non-crystalline forms of the
compound of formula (A1**) and chiral acids salts thereof.
The chiral acid salt (T*) of the compound of formula (A1) is
denoted to encompass all chiral acid salts of compound (A1) formed
in step (I) including the chiral acid salt (T) which precipitates
as well as all chiral acid salts formed which remain dissolved.
Thus, the chiral acid salt (T*) may comprise a mixture of chiral
acid salts of compounds of formula (A1*) and (A1**).
Preferably, in step (I) and (II), thus a chiral resolution of the
stereoisomers (A1*) and (A1**) is carried out.
As to the solvent used in step (I), any suitable organic solvent in
which the compound of formula (A1) is sufficiently soluble may be
used. In particular, the solvent is selected from the group
consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE,
CH.sub.2Cl.sub.2, ethyl acetate, acetone, isopropanol, methanol,
water, formic acid ethyl ester, isopropyl acetate, propyl acetate,
butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane,
methylisobutylketone, toluene, hexane, cyclohexane, heptane and
mixtures of two or more thereof. More preferably, the suitable
solvent comprises acetone or methanol, more preferably the suitable
solvent is acetone or methanol.
It is to be understood that in step (I) a further solvent may be
added in order to precipitate, preferably crystallize, the chiral
acid salt (T). In this case, the mixture obtained in (I) preferably
additionally comprises said further solvent.
This further solvent may be added prior to, together with or after
the addition of the chiral acid to the compound of formula (A1).
According to a preferred embodiment, the compound of formula (A1)
is dissolved in the suitable solvent mentioned above and a mixture,
preferably a solution of the chiral acid, in a further solvent is
added to the solution, wherein the further solvent and the suitable
solvent may be the same or may be different.
In particular, the further solvent is selected from the group
consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE,
CH.sub.2Cl.sub.2, ethyl acetate, acetone, isopropanol, methanol,
water, formic acid ethyl ester, isopropyl acetate, propyl acetate,
butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane,
methylisobutylketone, toluene, hexane, cyclohexane, heptane and
mixtures of two or more thereof. More preferably, the suitable
solvent comprises acetone or methanol, more preferably the further
solvent is acetone or methanol. More preferably, the suitable
solvent and the further solvent are the same, in particular both
comprise acetone or methanol, preferably both are acetone or
methanol.
Thus, the present invention also relates to a process for the
preparation of a chiral acid salt (T) of a compound of formula
(A1), as described above, and a chiral acid salt (T) of compound of
formula (A1), obtained or obtainable by said process, wherein step
(I) comprises dissolving the compound of formula (A1) in the
suitable solvent and adding a solution of the chiral acid dissolved
in a further solvent to the solution, wherein the further solvent
and the suitable solvent are preferably the same, more preferably
acetone or methanol.
Preferably, the compound of formula (A1) is dissolved in the
suitable solvent and the mixture is heated to a temperature in the
range of from 20 to 80.degree. C., more preferably to a temperature
in the range of from 30 to 60.degree. C., more preferably to a
temperature in the range of from 30 to 50.degree. C., more
preferably to a temperature in the range of from 30 to 40.degree.
C., prior to the addition of the tartaric acid. During the heating
step, the temperature may be varied, constantly or stepwise, or
held essentially constant. Preferably, the mixture is heated until
a clear solution of the compound of formula (A1) in the suitable
solvent is obtained. Optionally, the mixture is afterwards cooled
to room temperature.
The precipitation, preferably the crystallizing, in step (I) is
preferably carried out at a temperature in the range of from 0 to
60.degree. C., wherein the temperature is preferably continuously
or stepwise decreased during step (b). The chiral acid may thus
e.g. be added to a solution of the compound of formula (A1) in the
suitable solvent which has been previously heated or which has been
previously heated and afterwards cooled to a specific temperature,
or which has not been previously heated.
After the addition of the chiral acid derivative, and optionally
the further solvent, the mixture may again be heated or
alternatively be cooled, or the temperature may be held constant.
Preferably, the mixture is cooled to a temperature in the range of
from 0 to 50.degree. C., more preferably to a temperature in the
range of from 0 to 40.degree. C., more preferably to a temperature
in the range of from 10 to 30.degree. C.
Preferably, the mixture obtained in step (I) consists of the chiral
acid salt (T), optionally unreacted chiral acid derivative,
optionally unreacted compound of formula (A1), optionally further
chiral acid salts (salt (T*) minus the amount of precipitated
chiral acid salt (T), the suitable solvent and optionally the
further suitable solvent.
Step (II)
In the optional step (II) of the process of the invention, the
chiral acid salt (T) is separated from the mixture obtained in step
(I).
It is to be understood that, if the chiral acid is a tartaric acid
or tartaric acid derivative, a salt between two molecules of (A)
and one molecule of the chiral acid may be formed. Such salts are
thus encompassed by the term "the acid salt (T)". The separation
may be carried out by any suitable method known to those skilled in
the art. Preferably, the separating in step (II) is carried out by
centrifugation or filtration, preferably filtration.
It is to be understood that the separated salt may be subjected to
a further treatment such as an after-treatment such as a
purification step and/or lyophilization.
Preferably, the obtained chiral acid salt (T) of the compound
formula (A1) contains at least 95% by weight, more preferably at
least 96% by weight, more preferably at least 97% by weight, more
preferably at least 98% by weight, more preferably at least 99% by
weight, more preferably at least 99.5% by weight, more preferably
at least 99.9% by weight, of the tartaric salt of the compound of
formula (A1*), based on the total weight of chiral acid salt of the
compound of formula (A1), i.e. based on the sum of (A1**) and
(A1*). More preferably, the chiral acid salt (T) of the compound of
formula (A1) consists of the chiral acid salt of the compound of
formula (A1*).
Preferably, the chiral acid is a di-benzoyl tartaric acid or a
di-toluoyl tartaric acid.
According to a preferred embodiment, A1 is (Ia),
##STR00073## with R.sup.2.dbd.H, and consists of a mixture of (Ia*)
and (Ia**)
##STR00074## wherein R.sup.2.dbd.H. In this case, the chiral acid
is preferably or a di-toluoyl tartaric acid, more preferably
L-di-toluoyl tartaric acid (LTTA). Most preferably R.sup.2.dbd.H
and R.sup.1.dbd.H and the chiral acid is L-di-toluoyl tartaric
acid. In this case, the suitable solvent is preferably
methanol.
According to a further preferred embodiment, A1 is (Ib), with
R.sup.2.dbd.H, and consists of a mixture of (Ib*) and (Ib**)
##STR00075## wherein R.sup.2.dbd.H. In this case, the chiral acid
is preferably a di-benzoyl tartaric acid, more preferably
D-di-benzoyl tartaric acid (DBTA). Most preferably R.sup.2.dbd.H
and R.sup.1=Cbz and the chiral acid is D-di-benzoyl tartaric acid.
In this case, the suitable solvent is preferably acetone.
As mentioned above, the compound (A) is preferably being used for
the preparation of the compound of formula (IX) (Suvorexant). Thus,
the present invention also relates to a process for the preparation
of a compound of formula (IX), comprising (A) preparing a compound
of formula (A) as described hereinunder and above, wherein in case
n=0, at least one of R.sup.A or R.sup.B is H or a protecting group,
(B) transforming the compound (A) into the compound of formula
(IX).
According a preferred embodiment, compound (A) has the structure
(Ia), preferably (Ia*), with R.sup.1 being H and with R.sup.2 being
PG.sup.2. Thus, the present invention preferably relates to a
process for the preparation of a compound and a compound obtained
or obtainable by said process, the compound having the
structure
##STR00076## or being a pharmaceutically acceptable salt or solvate
thereof, wherein (Ia) is preferably (Ia*)
##STR00077## and wherein R.sup.1 is H and R.sup.2 is PG.sup.2, the
process comprising (a) providing a compound of formula (II),
##STR00078## preferably of formula (II*), wherein R.sup.E is
selected from the group consisting of H, alkyl, aryl, alkylaryl,
heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein
R.sup.E is alkyl, more preferably wherein R.sup.E is methyl, ethyl
or propyl, more preferably wherein R.sup.E is methyl, (b) reacting
the compound of formula (II), preferably of formula (II*), with a
base, to give the compound of formula (Ia), with R.sup.1 being H
and with R.sup.2 being PG.sup.2, preferably (Ia*) with R.sup.1
being H and with R.sup.2 being PG.sup.2.
Preferably, compound (Ia), with R.sup.1 being H and with R.sup.2
being PG.sup.2, thus compound
##STR00079## more preferably compound (Ia*) with R.sup.1 being H
and with R.sup.2 being PG.sup.2, thus compound
##STR00080## is used for the preparation of Suvorexant. Thus, the
present invention also relates to the use of the compound of
formula (Ia), preferably (Ia*), in which R.sup.1 is H and R.sup.2
is PG.sup.2, for the preparation of Suvorexant.
##STR00081##
Further, the present invention relates to a process for the
preparation of a compound of formula (IX) and a compound of formula
(IX) obtained or obtainable by said process comprising (A)
providing a compound of formula (Ia) by a process comprising (a)
providing a compound of formula (II)
##STR00082## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, and wherein R.sup.1 is H and
R.sup.2 is PG.sup.2, (b) reacting the compound of formula (II) with
a base, to give the compound of formula (Ia), with R.sup.1 being H
and with R.sup.2 being PG.sup.2, preferably (Ia*) with R.sup.1
being H and with R.sup.2 being PG.sup.2, (B) transforming the
compound of step (A) into the compound of formula (IX).
Preferably, step (B) comprises (c1) removal of the protecting group
PG.sup.2, (d1) reacting the compound of formula (Ia) with R.sup.1
and R.sup.2 being H with a compound of formula (XI)
##STR00083## wherein E is --COOH or a reactive carboxy group, to
give a compound of formula (VIIa) in which R.sup.1 is H,
##STR00084## preferably
##STR00085## (e1) reducing the compound, to give a compound of
formula (VIIb) in which R.sup.1 is H
##STR00086## preferably
##STR00087## preferably with a reducing agent selected from the
group consisting of NaBH.sub.4, NaCNBH.sub.3, NaBH(OAc).sub.3,
LiAlH.sub.4, LiBH.sub.4 and H.sub.2 in the presence of transition
metals, wherein the transition metal is preferably selected from
the group consisting of Ir, Pt, Fe, Rh, Pd, Re, Ru, Ni and Co, (f1)
reacting the compound of formula (VIIb), preferably (VIIb*) with a
compound of formula (XII)
##STR00088## wherein X* is a leaving group, preferably Cl.
In an embodiment, (e1) optionally comprises (e1-1) preparing a salt
of the compound of formula (VIIb) in which R.sup.1 is H, preferably
(VIIb*) in which R.sup.1 is H and preferably wherein the salt is an
hydrochloride salt or a sulphate salt, (e1-2) optionally purifying
the compound obtained in (e1) or (e1-1), wherein preferably
purifying comprises crystallizing the compound obtained in (e1) or
(e1-1), (e1-3) optionally transforming the crystalline salt of
(e1-2) in the free base of formula (VIIb), preferably (VIIb*).
Preferably, in step (e1-2), the crystalline form (A) or the
crystalline form (I) is obtained.
Preferably in step (e1-2), the crystalline form (I-S) or the
crystalline form (I-Cl) are obtained. Crystalline forms (A), (I),
(I-S) and (I-Cl) are disclosed herein below.
The present invention further relates to a compound obtained or
obtainable by said process (this includes a salt thereof). Further,
the present invention relates to a compound of formula (VIIa),
preferably (VIIa*), as mentioned above. Further the present
invention relates to a compound (VIIb), preferably (VIIb*), as
mentioned above.
The present invention relates to a compound of formula (VIIb) or a
salt thereof, more preferably (VIIb*), in which R.sup.1 is H, which
are in a crystalline form.
A crystalline form of the compound (VIIb) in which R.sup.1 is H is
crystalline form (A) and has an X-ray powder diffraction pattern
comprising a peak at 2-theta angle of approximately
12.4.degree..+-.0.2.degree.. Preferably, the crystalline form (A)
in which R.sup.1 is H has an X-ray powder diffraction pattern
comprising peaks at 2-theta angles of approximately
4.8.+-.0.2.degree., 12.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 19.9.degree..+-.0.2.degree. and
20.8.degree..+-.0.2.degree. or has an X-ray powder diffraction
pattern comprising peaks at 2-theta angles of approximately
7.7.+-.0.2.degree., 11.4.degree..+-.0.2.degree.,
12.4.degree..+-.0.2.degree., 16.2.degree..+-.0.2.degree. and
18.1.degree..+-.0.2.degree.. More preferably, the crystalline (A)
thereof in which R.sup.1 is H has an X-ray powder diffraction
pattern comprising peaks at 2-theta angles of approximately
4.8.+-.0.2.degree., 12.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 19.9.degree..+-.0.2.degree. and
20.8.degree..+-.0.2.degree.. The X-ray powder diffraction pattern
is as measured at a temperature in the range of from 15 to
25.degree. C. with Cu-K.alpha..sub.1,2 radiation having a
wavelength of 0.15419 nm.
Alternatively crystalline form (A) has an X-ray powder diffraction
pattern comprising a peak at 2-theta angle of approximately
12.4.degree..+-.0.2.degree., more preferably has an X-ray powder
diffraction pattern comprising peaks at 2-theta angles of
approximately 4.8.+-.0.2.degree., 12.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 19.9.degree..+-.0.2.degree. and
20.8.degree..+-.0.2. The X-ray preferably further comprises peaks
at one or more than one or all of 2-theta angles of
21.6.degree..+-.0.2.degree., 22.6.degree..+-.0.2.degree.
22.9.degree..+-.0.2 and 27.8.degree..+-.0.2. .degree. The X-ray
powder diffraction pattern is measured at a temperature in the
range of from 15 to 25.degree. C. with Cu-K.alpha..sub.1,2
radiation having a wavelength of 0.15419 nm.
A crystalline form of compound (VIIb*) wherein R.sup.1 is H is
crystalline form (I) and has an X-ray powder diffraction pattern
comprising a peak at 2-theta angle of approximately
11.3.degree..+-.0.2.degree., more preferably has an X-ray powder
diffraction pattern comprising peaks at 2-theta angles of
11.3.+-.0.2.degree., 12.3.degree..+-.0.2.degree.,
13.3.degree..+-.0.2.degree., 16.0.degree..+-.0.2.degree.,
20.0.+-.0.2.degree.. Preferably, the X-ray powder diffraction
pattern further comprises peaks at 2-theta angles of
16.5.+-.0.2.degree., 18.3. .degree..+-.0.2.degree.,
20.1.degree..+-.0.2.degree., 22.7.degree..+-.0.2.degree.. The X-ray
powder diffraction pattern is as measured at a temperature in the
range of from 15 to 25.degree. C. with Cu-K.alpha..sub.1,2
radiation having a wavelength of 0.15419 nm.
Compound of formula (VIIb) and of formula (VIIb*) or salt thereof
and the crystalline form thereof as disclosed below are preferably
obtained or obtainable by a process as described above,
wherein step (e1) preferably comprises
reducing the compound, to give a compound of formula (VIIb) in
which R.sup.1 is H
##STR00089## preferably
##STR00090## preferably with a reducing agent selected from the
group consisting of NaBH.sub.4, NaCNBH.sub.3, NaBH(OAc).sub.3,
LiAlH.sub.4, LiBH.sub.4 and H.sub.2 in the presence of transition
metals, wherein the transition metal is preferably selected from
the group consisting of IR, Pt, Fe, Rh, Pd, Re, Ru, Ni and Co, more
preferably wherein the reducing agent is selected from the group
consisting of NaBH.sub.4, NaCNBH.sub.3, NaBH(OAc).sub.3,
LiAlH.sup.4, and LiBH.sub.4, more preferably the reducing agent is
NaBH.sub.4, NaCNBH.sub.3 or NaBH(OAc).sub.3, more preferably
NaBH.sub.4, and crystallizing the crude product, preferably from a
mixture comprising heptane, ethyl acetate and NEt.sub.3 and
obtaining a crystalline compound of formula (VIIb), preferably of
formula (VIIb*).
Regarding the crystalline compound of formula (VIIb) and of formula
(VIIb*) wherein R.sup.1 is H they are preferably the crystalline
forms (A) and (I), respectively as disclosed above.
According to a further embodiment the process further comprises
preparing the salt of the crude product of the reduction step or of
the crystalline solid.
According to a further embodiment, the process further comprises
crystallizing the salt obtained.
Regarding the salt, the salt is preferably selected from the group
consisting of hydrochloride salt and sulphate salt. Preferably, the
salts are in a crystalline form.
Regarding the crystalline salts of compound of formula (VIIb*)
wherein R.sup.1 is H they are preferably in the crystalline forms
(I-S) and (I-Cl) as disclosed below.
Regarding the crystallizing of compound (VIIb) or (VIIb*)
preferably wherein R.sup.1 is H, the crystallizing is preferably
from a solvent, preferably an organic solvent, wherein preferably
the organic solvent is selected from the group consisting of ethyl
acetate, methanol, CH.sub.2Cl.sub.2, acetonitrile, isopropyl
acetate, acetone, ethanol, isopropanol, toluene, butanol,
isobutanol, t-butanol, tetrahydrofuran, methyltetrahydrofuran,
cyclohexane and mixture thereof. Preferably, when ethyl acetate is
used as the crystallization solvent of the compound of formula
(VIIb*) the crystalline form (I) is obtained.
Regarding the crystallizing of the salt compound (VIIb) or (VIIb*)
preferably wherein R.sup.1 is H, the crystallizing is preferably
from a solvent, preferably and organic solvent, wherein preferably
the organic solvent is selected from the group consisting of ethyl
acetate, methanol, CH.sub.2Cl.sub.2, acetonitrile, isopropyl
acetate, acetone, ethanol, isopropanol, toluene, butanol,
iso-butanol, t-butanol, tetrahydrofuran, methyltetrahydrofuran,
cyclohexane and mixture thereof. Preferably, when the solvent is
selected from the group consisting of ethyl acetate, methanol,
CH.sub.2Cl.sub.2, and mixture thereof, preferably a mixture of
methanol, CH.sub.2Cl.sub.2 is used as the crystallization solvent
of the sulphate salt of the compound of formula (VIIb*) the
crystalline form (I-S) is obtained. Preferably, when ethyl acetate
is used as the crystallization solvent of the hydrochloride salt of
the compound of formula (VIIb*) the crystalline form (I-Cl) is
obtained.
Regarding the crystallizing of compound (VIIb) or (VIIb*)
preferably wherein R.sup.1 is H, the crystallizing is preferably
carried out at a temperature in the range of from -30 to 70.degree.
C., more preferably in the range of from -10 to 50.degree. C., most
preferably in the range of from 10 to 30.degree. C.
Regarding the crystallizing of the salt compound (VIIb) or (VIIb*)
preferably wherein R.sup.1 is H, the crystallizing is preferably
carried out at a temperature in the range -30 to 70.degree. C.,
more preferably in the range of from -10 to 50.degree. C., most
preferably in the range of from 10 to 30.degree. C.
According to a further preferred embodiment, compound (A) has the
structure (Ib), preferably (Ib*), with R.sup.1 being H and with
R.sup.2 being PG.sup.2. Thus, the present invention preferably
relates to a process for the preparation of a compound and a
compound obtained or obtainable by said process the compound having
the structure
##STR00091## or being a pharmaceutically acceptable salt or solvate
thereof, wherein (Ib) is preferably (Ib*)
##STR00092## and wherein R.sup.1 is H and R.sup.2 is PG.sup.2, the
process comprising (a) providing a compound of formula (II),
##STR00093## preferably (II*), wherein R.sup.E is selected from the
group consisting of H, alkyl, aryl, alkylaryl, heteroaryl
cycloalkyl and heterocycloalkyl, more preferably wherein R.sup.E is
alkyl, more preferably wherein R.sup.E is methyl, ethyl or propyl,
more preferably wherein R.sup.E is methyl, (b) reacting the
compound of formula (II) with a base, and reducing the resulting
compound of formula (Ia), to give the compound of formula (Ib),
with R.sup.1 being H and with R.sup.2 being PG.sup.2, preferably
(Ib*) with R.sup.1 being H and with R.sup.2 being PG.sup.2.
Preferably, compound (Ib) with R.sup.1 being H and with R.sup.2
being PG.sup.2, thus compound
##STR00094## more preferably compound (Ib*) with R.sup.1 being H
and with R.sup.2 being PG.sup.2, thus compound
##STR00095## is used for the preparation of Suvorexant. Thus, the
present invention also relates to the use of the compound of
formula (Ib), preferably (Ib*), in which R.sup.1 is H and R.sup.2
is PG.sup.2, for the preparation of compound (IX) (Suvorexant)
##STR00096##
Further, the present invention relates to a process for the
preparation of a compound of formula (IX) comprising (A) providing
a compound of formula (Ib) by a process comprising (a) providing a
compound of formula (II),
##STR00097## preferably (II*), wherein R.sup.E is selected from the
group consisting of H, alkyl, aryl, alkylaryl, heteroaryl
cycloalkyl and heterocycloalkyl, more preferably wherein R.sup.E is
alkyl, more preferably wherein R.sup.E is methyl, ethyl or propyl,
more preferably wherein R.sup.E methyl, wherein R.sup.1 is H and
R.sup.2 is PG.sup.2, (b) reacting the compound of formula (II) with
a base, to give the compound of formula (Ia),
##STR00098## with R.sup.1 being H and with R.sup.2 being PG.sup.2,
preferably (Ia*) with R.sup.1 being H and with R.sup.2 being
PG.sup.2, and reducing the resulting compound of formula (Ia),
preferably (Ia*). (B) transforming the compound of step (A) into
the compound of formula (IX).
Preferably, step (B) comprises (c1) removal of the protecting group
PG.sup.2, (d1b) reacting the compound of formula (Ib) with R.sup.1
and R.sup.2 being H with a compound of formula
##STR00099## wherein E is --COOH or a reactive carboxy group, to
give a compound of formula (VIIb) in which R.sup.1 is H
##STR00100## preferably
##STR00101## (f1) reacting the compound of formula (VIIb),
preferably (VIIb*) with a compound of formula (XII)
##STR00102## wherein X* is a leaving group, preferably Cl.
In an embodiment (d1b) optionally comprises (d1b-1) optionally
preparing a salt of the compound of formula (VIIb) in which R.sup.1
is H, preferably (VIIb*) in which R.sup.1 is H and preferably
wherein the salt is an hydrochloride salt or a sulphate salt,
(d1b-2) optionally purifying the compound obtained in (d1b) or
(d1b-1), wherein preferably purifying comprises crystallizing the
compound obtained in (d1b) or (d1b-1), (d1b-3) optionally
transforming the crystalline salt of (d1b-2) in the free base of
formula (VIIb), preferably (VIIb*).
Preferably, in step (d1b-2), the crystalline form (A) or the
crystalline form (I) is obtained. Preferably in step (d1b-2), the
crystalline form (I-S) or the crystalline form (I-Cl) are obtained.
Crystalline forms (A), (I), (I-S) and (I-Cl) are disclosed herein
below.
The present invention further relates to a compound obtained or
obtainable by said process.
According to a further preferred embodiment, compound (A) has the
structure (Ia), preferably (Ia*), with R.sup.1 being H and with
R.sup.2 being
##STR00103## i.e. the structure (VIIa), preferably (VIIa*), with
R.sup.1 being H.
Thus, the present invention preferably relates to a process for the
preparation of a compound, and a compound obtained or obtainable by
said process, the compound having the structure (Vila), preferably
(VIIa*), with R.sup.1 being H,
the process comprising
(a) providing a compound of formula (II),
##STR00104## preferably (II*), wherein R.sup.E is selected from the
group consisting of H, alkyl, aryl, alkylaryl, heteroaryl
cycloalkyl and heterocycloalkyl, more preferably wherein R.sup.E is
alkyl, more preferably wherein R.sup.E is methyl, ethyl or propyl,
more preferably wherein R.sup.E is methyl, and wherein R.sup.2
is
##STR00105## (b) reacting the compound of formula (II), preferably
(II*), with a base to give the compound of formula (VIIa),
preferably (VIIa*).
Preferably, compound (Vila), preferably (VIIa*), with
R.sup.1.dbd.H, is used for the preparation of compound (IX)
(Suvorexant).
Thus, the present invention also relates to the use of a compound
(VIIa), preferably (VIIa*), with R.sup.1.dbd.H, for the preparation
of compound (IX)
##STR00106##
Further, the present invention relates to a process for the
preparation of a compound of formula (IX) comprising (A) providing
a compound of formula (VIIa) by a process comprising (a) providing
a compound of formula (II)
##STR00107## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E alkyl, more
preferably wherein R.sup.E methyl, ethyl or propyl, more preferably
wherein R.sup.E methyl, and wherein R.sup.2 is
##STR00108## (b) reacting the compound of formula (II) with a base,
to give the compound (Vila), preferably (VIIa*), with
R.sup.1.dbd.H, (B) transforming the compound of step (A) into the
compound of formula (IX).
Preferably, step (B) further comprises (e1) reducing the compound
to give a compound of formula (VIIb) in which R.sup.1 is H,
preferably (VIIb*) in which R.sup.1 is H, (f1) reacting the
compound of formula (VIIb), preferably (VIIb*), with a compound of
formula (XII)
##STR00109## wherein X* is a leaving group, preferably Cl,
In an embodiment, (e1) optionally comprises (e1-1) optionally
preparing a salt of the compound of formula (VIIb) in which R.sup.1
is H, preferably (VIIb*) in which R.sup.1 is H and preferably
wherein the salt is an hydrochloride salt or a sulphate salt,
(e1-2) optionally purifying the compound obtained in (e1) or
(e1-1), wherein preferably purifying comprises crystallizing the
compound obtained in (e1) or (e1-1), (e1-3) optionally transforming
the crystalline salt of (e1-2) in the free base of formula (VIIb),
preferably (VIIb*).
Preferably, in step (e1-2), the crystalline form (A) or the
crystalline form (I) is obtained. Preferably in step (e1-2), the
crystalline form (I-S) or the crystalline form (I-Cl) are obtained.
Crystalline forms (A), (I), (I-S) and (I-Cl) are disclosed herein
below.
The present invention further relates to a compound obtained or
obtainable by said process. Further, the present invention relates
to a compound of formula (VIIb), preferably (VIIb*), as mentioned
above. Further the present invention relates to the use of a
compound (VIIb), preferably (VIIb*), as mentioned above.
According a further preferred embodiment, compound (A) has the
structure (Ib), preferably (Ib*), with R.sup.1 being H and with
R.sup.2 being
##STR00110## i.e. the structure (VIIb), preferably (VIIb*), with
R.sup.1 being H.
Thus, the present invention preferably relates to a process for the
preparation of a compound, and a compound obtained or obtainable by
said process, the compound having the structure (VIIa), preferably
(VIIa*), with R.sup.1 being H,
the process comprising
(a) providing a compound of formula (II),
##STR00111## preferably (II*), wherein R.sup.E is selected from the
group consisting of H, alkyl, aryl, alkylaryl, heteroaryl,
cycloalkyl and heterocycloalkyl, more preferably wherein R.sup.E is
alkyl, more preferably wherein R.sup.E is methyl, ethyl or propyl,
more preferably wherein R.sup.E is methyl, and wherein R.sup.2
is
##STR00112## (b) reacting the compound of formula (II), preferably
(II*), with a base, and reducing the resulting compound to give a
compound of formula (VIIb), preferably (VIIb*).
In an embodiment, (b) optionally further comprises (b1-1)
optionally preparing a salt of the compound of formula (VIIb) in
which R.sup.1 is H, preferably (VIIb*) in which R.sup.1 is H and
preferably wherein the salt is an hydrochloride salt or a sulphate
salt, (b1-2) purifying the compound obtained in (b) or (b1-1),
wherein preferably purifying comprises crystallizing the compound
obtained in (b) or (b1-1), (b1-3) optionally transforming the
crystalline salt of (b1-2) in the free base of formula (VIIb),
preferably (VIIb*).
Preferably, in step (b1-2), the crystalline form (A) or the
crystalline form (I) is obtained. Preferably, in step (b1-2), the
crystalline form (I-S) or the crystalline form (I-Cl) are obtained.
Crystalline forms (A), (I), (I-S) and (I-Cl) are disclosed herein
below.
Preferably, compound (VIIb), preferably (VIIb*), with
R.sup.1.dbd.H, is used for the preparation of Suvorexant.
Thus, the present invention also relates to the use of compound
(VIIb), preferably (VIIb*), with R.sup.1.dbd.H, for the preparation
of compound (IX)
##STR00113##
Further, the present invention relates to a process for the
preparation of a compound of formula (IX) comprising (A) providing
a compound of formula (VIIb) by a process comprising (a) providing
a compound of formula (II), preferably (II*).
##STR00114## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, and wherein R.sup.2 is
##STR00115## (b) reacting the compound of formula (II), preferably
(II*), with a base to give the compound of formula (Vila),
preferably (VIIa*), and reducing the resulting compound to give a
compound of formula (VIIb), preferably (VIIb*), (B) transforming
the compound of step (A) into the compound of formula (IX).
In an embodiment, (b) optionally further comprises (b1-1)
optionally preparing a salt of the compound of formula (VIIb) in
which R.sup.1 is H, preferably (VIIb*) in which R.sup.1 is H and
preferably wherein the salt is an hydrochloride salt or a sulphate
salt, (b1-2) optionally purifying the compound obtained in (b) or
(b1-1), wherein preferably purifying comprises crystallizing the
compound obtained in (b) or (b1-1), (b1-3) optionally transforming
the crystalline salt of (b1-2) in the free base of formula (VIIb),
preferably (VIIb*).
Preferably, in step (b1-2), the crystalline form (A) or the
crystalline form (I) is obtained. Preferably, in step (b1-2), the
crystalline form (I-S) or the crystalline form (I-Cl) are obtained.
Crystalline forms (A), (I), (I-S) and (I-Cl) are disclosed herein
below.
Preferably, step (B) comprises (f1) reacting the compound of
formula (VIIb), preferably (VIIb*), with a compound of formula
(XII)
##STR00116## wherein X* is a leaving group, preferably Cl.
The present invention further relates to a compound obtained or
obtainable by said process.
According a further preferred embodiment, compound (A) has the
structure (Ia), preferably (Ia*), with R.sup.1 being R.sup.A and
with R.sup.2 being PG.sup.2. Preferably, R.sup.A is
##STR00117##
Thus, the present invention preferably relates to a process for the
preparation of a compound, and a compound obtained or obtainable by
said process, the compound having the structure
##STR00118## or being a pharmaceutically acceptable salt or solvate
thereof, wherein (Ia) is preferably (Ia*)
##STR00119## and wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00120## and R.sup.2 is PG.sup.2, the process comprising (a)
providing a compound of formula (II)
##STR00121## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, wherein R.sup.1 is R.sup.A
with R.sup.A being
##STR00122## and R.sup.2 is PG.sup.2, preferably the compound of
formula (Ia*), wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00123## and R.sup.2 is PG.sup.2, (b) reacting the compound of
formula (II) with a base, to give the compound of formula (Ia),
wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00124## and R.sup.2 is PG.sup.2, preferably the compound of
formula (Ia*), wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00125## and R.sup.2 is PG.sup.2.
The compound of formula (Ia) wherein R.sup.1 is R.sup.A with
R.sup.A being
##STR00126## and wherein R.sup.2 is PG.sup.2 is hereinunder and
above referred to as compound (VIIIa)
##STR00127## the respective single isomer as (VIIIa*)
##STR00128##
Preferably, compound (VIIIa), more preferably compound (VIIIa*), is
used for the preparation of Suvorexant. Thus, the present invention
also relates to the use of compound (VIIIa), more preferably of
compound (VIIIa*), for the preparation of Suvorexant
##STR00129##
Further, the present invention relates to a process for the
preparation of a compound of formula (IX) comprising (A) providing
a compound of formula (VIIIa) by a process comprising (a) providing
the compound of formula (II),
##STR00130## preferably (II*), wherein R.sup.E is selected from the
group consisting of H, alkyl, aryl, alkylaryl, heteroaryl
cycloalkyl and heterocycloalkyl, more preferably wherein R.sup.E is
alkyl, more preferably wherein R.sup.E is methyl, ethyl or propyl,
more preferably wherein R.sup.E is methyl, wherein R.sup.1 is
R.sup.A with R.sup.A being
##STR00131## and R.sup.2 is PG.sup.2, preferably the compound of
formula (Ia*), wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00132## and R.sup.2 is PG.sup.2, (b) reacting the compound of
formula (II) with a base, to give the compound of formula (VIIIa),
preferably (VIIIa*), (B) transforming the compound of step (A) into
the compound of formula (IX).
Preferably, step (B) further comprises (c1) removal of the
protecting group PG.sup.2, (d1) reacting the compound of formula
(VIIIa), preferably the compound of formula (VIIIa*), with a
compound of formula
##STR00133## wherein E is --COOH or a reactive carboxy group, to
give a compound
##STR00134## preferably a compound
##STR00135## (e1) reducing the compound obtained in (f1).
The present invention further relates to a compound obtained or
obtainable by said process. Further, the present invention relates
to a compound of formula (VIIIa), preferably (VIIIa*), as mentioned
above. Further the present invention relates to the use of a
compound (VIIIa), preferably (VIIIa*), as mentioned above.
According to a further preferred embodiment, compound (A) has the
structure (Ib), preferably (Ib*), with R.sup.1 being R.sup.A and
with R.sup.2 being PG.sup.2. Preferably, R.sup.A is
##STR00136##
Thus, the present invention preferably relates to a process for the
preparation of a compound, and a compound obtained or obtainable by
said process, the compound having the structure
##STR00137## or being a pharmaceutically acceptable salt or solvate
thereof, wherein (Ib) is preferably (Ib*)
##STR00138## and wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00139## and R.sup.2 is PG.sup.2, the process comprising (a)
providing a compound of formula (II)
##STR00140## preferably (II*), wherein R.sup.E is selected from the
group consisting of H, alkyl, aryl, alkylaryl, heteroaryl,
cycloalkyl and heterocycloalkyl, more preferably wherein R.sup.E is
alkyl, more preferably wherein R.sup.E is methyl, ethyl or propyl,
more preferably wherein R.sup.E is methyl, wherein R.sup.1 is
R.sup.A with R.sup.A being
##STR00141## and R.sup.2 is PG.sup.2, preferably the compound of
formula (Ia*), wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00142## and R.sup.2 is PG.sup.2, (b) reacting the compound of
formula (II) with a base, and reducing the compound to give the
compound of formula (Ib), wherein R.sup.1 is R.sup.A with R.sup.A
being
##STR00143## and R.sup.2 is PG.sup.2, preferably the compound of
formula (Ib*), wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00144## and R.sup.2 is PG.sup.2.
The compound of formula (Ib) wherein R.sup.1 is R.sup.A with
R.sup.A being
##STR00145## and wherein R.sup.2 is PG.sup.2 is hereinunder and
above referred to as compound (VIIIb)
##STR00146## the respective single isomer as (VIIIb*)
##STR00147##
Preferably, compound (VIIIb), more preferably compound (VIIIb*), is
used for the preparation of compound (IX). Thus, the present
invention also relates to the use of compound (VIIIb), more
preferably of compound (VIIIb*), for the preparation of compound
(IX).
##STR00148##
Further, the present invention relates to a process for the
preparation of the compound of formula (IX) comprising (A)
providing a compound of formula (VIIIb) by a process comprising (a)
providing a compound of formula (II), preferably (II*),
##STR00149## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, wherein R.sup.1 is R.sup.A
with R.sup.A being
##STR00150## and R.sup.2 is PG.sup.2, preferably the compound of
formula (Ia*), wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00151## and R.sup.2 is PG.sup.2, (b) reacting the compound of
formula (II), preferably (II*), with a base, to give the compound
of formula (VIIIa), preferably (VIIIa*), and reducing the compound
of formula (VIIIa), preferably (VIIIa*), to give the compound of
formula (VIIIb), preferably (VIIIb*), (B) transforming the compound
of step (A) into the compound of formula (IX).
Preferably, step (B) further comprises (c1) removal of the
protecting group PG.sup.2, (d1b) reacting the compound of formula
(VIIIb), preferably the compound of formula (VIIIb*), with a
compound of formula
##STR00152## wherein E is --COOH or a reactive carboxy group.
The present invention further relates to a compound obtained or
obtainable by said process. Further, the present invention relates
to a compound of formula (VIIIb), preferably (VIIIb*), as mentioned
above. Further the present invention relates to the use of a
compound (VIIIb), preferably (VIIIb*), as mentioned above.
According to a further preferred embodiment, compound (A) has the
structure (Ia), preferably (Ia*), with R.sup.1 being R.sup.A and
with R.sup.2 being R.sup.B
##STR00153##
Thus, the present invention preferably relates to a process for the
preparation of a compound, and a compound obtained or obtainable by
said process, the compound having the structure
##STR00154## or being a pharmaceutically acceptable salt or solvate
thereof, wherein (Ia) is preferably (Ia*)
##STR00155## and wherein R.sup.1 is R.sup.A and R.sup.2 is
R.sup.B,
##STR00156## the process comprising (a) providing a compound of
formula (II)
##STR00157## and wherein R.sup.1 is R.sup.A and R.sup.2 is
R.sup.B,
##STR00158## (b) reacting the compound of formula (II) with a base,
to give the compound of formula (Ia), and wherein R.sup.1 is
R.sup.A and R.sup.2 is R.sup.B,
##STR00159##
The compound of formula (Ia) wherein R.sup.1 is R.sup.A and R.sup.2
is R.sup.B,
##STR00160## is hereinunder and above referred to as compound
(VIIIa)
##STR00161## the respective single isomer as (IXa*)
##STR00162##
Preferably, compound (IXa), more preferably compound (IXa*), is
used for the preparation of compound (IX). Thus, the present
invention also relates to the use of compound (IXa), more
preferably compound of (IXa*), for the preparation of compound
(IX)
##STR00163##
Further, the present invention relates to a process for the
preparation of compound IX comprising (A) providing a compound of
formula (IXa*) by a process comprising (a) providing a compound of
formula (II), preferably (II*),
##STR00164## wherein R.sup.1 is R.sup.A and R.sup.2 is R.sup.B,
##STR00165## (b) reacting the compound of formula (II), preferably
(II*), with a base, to give the compound of formula (IXa),
preferably (IXa*), (B) transforming the compound of step (A) into
the compound of formula (IX).
Preferably, step (B) further comprises (e1) reducing the
compound.
The present invention further relates to a compound obtained or
obtainable by said process. Further, the present invention relates
to a compound of formula (IXa), preferably (IXa*), as mentioned
above. Further the present invention relates to the use of a
compound (IXa), preferably (IXa*), as mentioned above.
Step (c1): Removal of the Protecting Group PG.sup.2
In step (c1) mentioned above, the protecting group PG.sup.2 is
removed. The way of removing the protecting group PG.sup.2 depends
on the protecting group used. Suitable methods are known to those
skilled in the art. Preferably, in case the protecting group
R.sup.2 is a Cbz protecting group, the removal of PG.sup.2 is
carried out under reductive conditions. More preferably, the
removal is carried out with hydrogen and a metal catalyst,
preferably a palladium catalyst, more preferably, the protecting
group is removed with Pd/C. The removal of group PG.sup.2 may be
carried out in any suitable solvent known to those skilled in the
art. Preferably, the reaction is carried out in an organic solvent,
more preferably in a solvent selected from the group consisting of
methanol, ethanol, iPrOH, nPrOH, EtOAc, iPrOAc and mixtures of two
or more thereof.
Preferably, the removal of group PG.sup.2 is carried out at a
temperature in the range of from 0.degree. C. to 100.degree. C.,
more preferably in the range of from 10.degree. C. to 70.degree.
C., more preferably at room temperature 20.degree. C. to 50.degree.
C. During the reaction, the temperature may be varied or held
essentially constant.
In case hydrogen is used, the reaction is preferably carried out at
a pressure in the range of from 1 to 4 bar, more preferably, 1.0 to
2.5 bar.
The compound is preferably allowed to react for a time in the range
of from 10 min to 180 min, more preferably in the range of from 20
to 120 min, more preferably in the range of from 30 to 60 min.
Step (d1):
In step (d1), the respective compound is reacted, i.e. coupled,
with a compound of formula (XI), wherein E is --COOH or a reactive
carboxy group, to give a compound of formula (VIIa) in which
R.sup.1 is H, preferably a compound of formula (VIIa*) in which
R.sup.1 is H.
The term "reactive carboxy group" as used in this context of the
present invention is intended to mean an activated carboxylic acid
derivative that reacts readily with electrophilic groups, such as
an NH group, optionally in the presence of a suitable base, in
contrast to those groups that require a further catalyst, such as a
coupling reagent, in order to react. The term "activated carboxylic
acid derivative" as used herein preferably refers to acid halides,
such as acid chlorides, and also refers to activated ester
derivatives including, but not limited to, formic and acetic acid
derived anhydrides, anhydrides derived from alkoxycarbonyl halides,
such as isobutyloxycarbonylchloride and the like, isothiocyanates
or isocyanates, anhydrides derived from reaction of the carboxylic
acid with N,N'-carbonyldiimidazole and the like, and esters derived
from activation of the corresponding carboxylic acid with a
coupling reagent. Such coupling reagents include, but are not
limited to, HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate); HOAt, HBTU
(O-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate); TBTU
(2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate); TFFH
(N,N',N'',N''-tetramethyluronium-2-fluoro-hexafluorophosphate); BOP
(benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate); PyBOP
(benzotriazol-1-yl-oxy-trispyrrolidino-phosphonium
hexafluorophosphate; EEDQ
(2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline); DCC
(dicyclohexylcarbodiimide); DIPCDI (diisopropylcarbodiimide); HOBt
(1-hydroxybenzotriazole); NHS (N-hydroxysuccinimide); MSNT
(1-(mesitylene-2-sulfonyl)-3-nitro-1H-1,2,4-triazole); aryl
sulfonyl halides, e.g. triisopropylbenzenesulfonyl chloride, EDC
(1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, CDC
(1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide), Pyclop, T3P, CDI,
Mukayama's reagent, HODhbt, HAPyU, TAPipU, TPTU, TSTU, TNTU, TOTU,
BroP, PyBroP, BOI, TOO, NEPIS, BBC, BDMP, BOMI, AOP, BDP, PyAOP,
TDBTU, BOP-Cl, CIP, DEPBT, Dpp-Cl, EEDQ, FDPP, HOTT, TOTT,
PyCloP.
In case E is --COOH, the reaction is preferably carried out in the
presence of a catalyst, such as a coupling reagent, or a reagent
that forms in situ an acid chlorid with E, such as oxalyl chloride,
and preferably further in the presence of a base. Preferably, in
this case, the coupling reagent is selected from the group
consisting of HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate); HOAt, HBTU
(O-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate); TBTU
(2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate); TFFH
(N,N',N'',N''-tetramethyluronium-2-fluoro-hexafluorophosphate); BOP
(benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate); PyBOP
(benzotriazol-1-yl-oxy-trispyrrolidino-phosphonium
hexafluorophosphate; EEDQ
(2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline); DCC
(dicyclohexylcarbodiimide); DIPCDI (diisopropylcarbodiimide); HOBt
(1-hydroxybenzotriazole); NHS (N-hydroxysuccinimide); MSNT
(1-(mesitylene-2-sulfonyl)-3-nitro-1H-1,2,4-triazole); aryl
sulfonyl halides, e.g. triisopropylbenzenesulfonyl chloride, EDC
(1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, CDC
(1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide), Pyclop, T3P, CDI,
Mukayama's reagent, HODhbt, HAPyU, TAPipU, TPTU, TSTU, TNTU, TOTU,
BroP, PyBroP, BOI, TOO, NEPIS, BBC, BDMP, BOMI, AOP, BDP, PyAOP,
TDBTU, BOP-Cl, CIP, DEPBT, Dpp-Cl, EEDQ, FDPP, HOTT, TOTT,
PyCloP.
More preferably, E is a reactive carboxy group, in particular
--C(.dbd.O)R.sup.5, wherein R.sup.5 is selected from the group
consisting of --O-Alkyl, --OH, --H and X with X being the leaving
group of the activated ester group --C(.dbd.O)--X, preferably
wherein X is selected from the group consisting of
##STR00166##
According to an alternative embodiment, E is --COOH, as mentioned
above, and the reaction includes the addition of a coupling reagent
or a reagent that forms in situ an acid chlorid with E, such as
oxalyl chloride.
The coupling with E being --COOH or a reactive carboxy group, is
preferably carried out in the presence of a suitable base,
preferably an organic base, most preferably an amino group
comprising base, most preferably a base selected from the group
consisting of diisopropylamine (DIEA), triethylamine (TEA),
N-methylmorpholine, N-methylimidazole,
1,4-diazabicyclo[2.2.2]octane (DABCO), N-methylpiperidine,
N-methylpyrrolidine, 2,6-lutidine, collidine, pyridine,
4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
As regards the reaction conditions used in this coupling step,
preferably, the reaction is carried out in an organic solvent, such
as N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO),
acetonitrile, acetone, dimethyl acetamide (DMA), dimethyl formamide
(DMF), formamide, tetrahydrofuran (THF), 1,4-dioxane, diethyl
ether, tert.-butyl methyl ether (MTBE), dichloromethane (DCM),
chloroform, tetrachloromethane and mixtures of two or more thereof.
More preferably, the reaction is carried out in
dichloromethane.
The temperature of the coupling reaction is preferably in the range
of from 0 to 100.degree. C., more preferably in the range of from 5
to 50.degree. C., and especially preferably in the range of from 15
to 30.degree. C. During the course of the reaction, the temperature
may be varied, preferably in the above given ranges, or held
essentially constant.
Step (d1a):
In step (d1a), the respective compound is reacted, i.e. coupled,
with a compound of formula (XI), wherein E is --COOH or a reactive
carboxy group. With respect to details regarding group E and
preferred reaction conditions, reference is made to the details
presented above and below with respect to step (d1) which equally
apply for step (d1a).
Step (e1): Reducing the compound of formula (VIIb):
In step (e1), the compound is reduced. In this case, a reduction of
the carbonyl group is thus carried out. The reduction is preferably
carried out as described with respect to step (b3) described
hereunder and above. Preferably, the reduction is carried out in an
organic solvent, more preferably in a solvent selected from the
group consisting of methanol, ethanol, nPrOH, i-PrOH, THF, 2-MeTHF,
MTBE, DIPET, toluene, acetonitrile, CH.sub.2Cl.sub.2 and mixtures
of two or more thereof.
Preferably, step (b3) is carried out at a temperature in the range
of from -20.degree. C. to 110.degree. C.
Preferably, step (e1) is carried out at a temperature in the range
of from -20.degree. C. to 110.degree. C.
Preferably, in step (e1, the compound is reduced by reaction with a
reducing agent selected from the group consisting of NaBH.sup.4,
NaCNBH.sub.3, NaBH(OAc).sub.3, LiAlH.sub.4, LiBH.sub.4 and H.sub.2
in the presence of transition metals, wherein the transition metal
is preferably selected from the group consisting of IR, Pt, Fe, Rh,
Pd, Re, Ru, Ni and Co. More preferably, the reducing agent is
selected from the group consisting of NaBH.sub.4, NaCNBH.sub.3,
NaBH(OAc).sub.3, LiAlH.sub.4 and LiBH.sub.4, more preferably the
reducing agent is NaBH.sub.4, NaCNBH.sub.3 or NaBH(OAc).sub.3, more
preferably NaBH.sub.4.
Step (f1):
In step (f1), the respective compound is reacted with a compound of
formula (XII)
##STR00167## wherein X* is a leaving group. The term leaving group
is denoted to encompass any group that departs upon reaction of
compound (XII) with an amine. Preferred leaving groups are --Cl,
--S, --SMe, --SEt or --Br, in particular --Cl or --Br.
Preferably, the reaction is carried out in an organic solvent, more
preferably in a solvent selected from the group consisting of
dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol,
isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran,
2-methyltetrahydrofuran, methyltertbutylether, diethylether,
diisopropylether, toluene, acetonitrile and mixtures of two or more
thereof.
Preferably, the reaction is carried out at a temperature in the
range of from 0 to 80.degree. C., more preferably in the range of
from 10 to 50.degree. C., more preferably in the range of from 20
to 35.degree. C., more preferably at room temperature. During the
reaction, the temperature may be varied or held essentially
constant.
The compounds are preferably allowed to react for a time in the
range of from 10 min to 72 h, more preferably in the range of from
30 min to 24 h, more preferably in the range of from 1 h to 12
h.
It is to be understood that after any one of the above-mentioned
steps it is conceivable that the reaction mixture obtained is
subjected to a suitable work-up, such as an isolation of the
respective compound. Such working up may comprise one or more
stages wherein preferably at least one stage comprises
purification, such as an extraction and/or a precipitation and/or
filtration and/or chromatography or the like. Alternatively, some
reactions may be carried out with the crude intermediate products
or even in situ.
Steps (b1-1), (e1-1)(d1b1)
In steps (b1-1), (e1-1) (d1-b1) a salt of the compound of formula
(VIIb) in which R.sup.1 is H, preferably (VIIb*) in which R.sup.1
is H and preferably wherein the salt is an hydrochloride salt or a
sulphate salt is prepared.
Steps (b1-2), (e1-2) (d1b-2)
In steps (b1-2), (e1-2) (d1-b2) the compound obtained in (b), (e1),
(d1b), (b1-1), (e1-1), (d1b-1) is purified. Preferably the
purifying comprises crystallizing the compound obtained (b), (e1),
(d1b), (b1-1), (e1-1), (d1b-1). Any method suitable for purifying
and crystallizing is according to the invention.
Preferably, the crystallizing is carried out in a solvent selected
from the group consisting of ethyl acetate, methanol,
CH.sub.2Cl.sub.2, acetonitrile, isopropyl acetate, acetone,
ethanol, isopropanol, toluene, butanol, isobutanol, t-butanol,
tetrahydrofuran, methyltetrahydrofuran, cyclohexane and mixture
thereof, wherein the solvent is preferably selected from the group
consisting of ethyl acetate, methanol, CH.sub.2Cl.sub.2 and a
mixture thereof.
Regarding the temperature of the crystallization process there is
no specific limitation provided that the crystalline form is
obtained. Preferably the temperature is in the range of from -30 to
70.degree. C., more preferably in the range of from 10 to
50.degree. C., even more in the range of from 10 to 30.degree.
C.
Steps (b1-3), (e1-3) (d1b-3)
In steps (b1-3), (e1-3) (d1-b3) the salt of (b1-2), (e1-2) (d1b-2)
or the crystalline salt of (b1-2), (e1-2) (d1b-2) is transformed in
the free base of formula (VIIb), preferably (VIIb*) according to
methods known in the art.
Step (a)
The compound of formula (II) may be provided by any suitable method
known to those skilled in the art.
Preferably, compound (II) provided in step (a) according to the
invention comprises (a1) reacting a compound of formula (III)
##STR00168## with a compound of formula (IV)
##STR00169## to give a compound of formula (V)
##STR00170## wherein at each occurrence R.sup.1a is H, PG.sup.1,
R.sup.A or PG.sup.1a and wherein R.sup.2a is H, PG.sup.2, R.sup.B
or PG.sup.2a and wherein PG.sup.1a and PG.sup.2a are, independently
of each other, suitable protecting groups and R.sup.E is as defined
above, (a2) optionally purifying the compound of formula (V), (a3)
reducing the compound of formula (V), (a4) optionally replacing
R.sup.2a and/or R.sup.1a with R.sup.1 and/or R.sup.2, to give the
compound of formula (II). Compound (II) and Compound (II*)
The compound of formula (II) provided in step (a) has the
structure
##STR00171## Residue R.sup.E
As described above, R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and
heterocycloalkyl, more preferably R.sup.E is selected from the
group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl
and heterocycloalkyl, more preferably R.sup.E is alkyl, more
preferably R.sup.E is methyl, ethyl or propyl, more preferably
R.sup.E methyl.
The structure
##STR00172## means that compound (II) has either the structure
##STR00173## or consists of a mixture of
##STR00174##
Alternatively, in step (a), the compound of formula (II*) is
provided, thus the "single (isolated) isomer" with R configuration.
The term "single isomer" in this context is denoted to mean that
the compound of formula (II*) comprises less than 1% by weight of
compound (II**), preferably less than 0.5% by weight, more
preferably less than 0.1% by weight, more preferably less than
0.05% by weight, more preferably less than 0.01% by weight, more
preferably essentially no, more preferably no compound of formula
(II**) based on the total weight of (II*) and (II**).
In case the compound of formula (II*) is provided in step (a), the
provision preferably either comprises a chiral resolution step or
an enantioselective reaction step, such as enantioselective
reduction of the double bond present in compound (V).
The chiral resolution may be carried out by any suitable method
known to those skilled in the art, such as resolution by
crystallization or by chiral chromatography, such as chiral HPLC.
Preferably, the chiral resolution during step (a) is carried out by
crystallization employing an optical pure resolving agent,
preferably an optical pure chiral acid. Preferably, the chiral
resolution of compound (II), if carried out, is carried out with a
tartaric acid as chiral acid, preferably with tartaric acid.
Preferably, the provision in step (a) comprises the steps (a1) to
(a4), as mentioned above.
Step (a3)
In step (a3), the compound of formula (V) is reduced to give a
compound having the structure
##STR00175##
Thus, compound of formula (IIa), is prepared by a process, the
process comprising steps (a1) to (a3) as disclosed above.
In case the reduction is carried out in a non-stereoselective
manner, compound (IIa) consists of a mixture of (IIa*) and (IIa**)
as shown below
##STR00176##
The reduction may be carried out by any suitable manner known to
those skilled in the art. Preferably, a metal catalyst and hydrogen
is used. The metal catalyst is preferably selected from the group
consisting of a catalyst comprising Pd, Fe, Ir, Rh or a mixture of
two or more thereof. Preferably, the catalyst comprises Pd and/or
Fe and/or Rh, wherein the Fe, if present, is preferably present as
part of a catalyst ligand.
The reaction is preferably carried out at a hydrogen pressure in
the range of from 1 to 25 bar, more preferably, 2.5 to 10 bar.
During the reaction, the pressure may be varied or held essentially
constant.
Preferably, the reaction is carried out at a temperature in the
range of from 10 to 100.degree. C., more preferably in the range of
from 20 to 60.degree. C., more preferably at 40 to 60 C. During the
reaction, the temperature may be varied or held essentially
constant.
The reaction may be carried out in any suitable solvent known to
those skilled in the art. Preferably, the cyclization reaction is
carried out in an organic solvent, more preferably in a solvent
selected from the group consisting of methanol, ethanol,
trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol,
ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol,
tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether,
diethylether, diisopropylether, toluene, acetonitrile and mixtures
of two or more thereof. Preferably, the solvent is methanol or
TFE.
According to one preferred embodiment, the catalyst is a palladium
catalyst, more preferably Pd/C. In case of Pd/C, the reaction is
preferably carried out in a non-stereoselective manner. The term
"non-stereoselective manner" is denoted to mean that a racemic
mixture of compounds (IIa*) and (IIa**) is obtained. Thus, the
present invention also relates to a process, as described above,
wherein step (a) comprises the steps (a1) to (a4), as described
above, and wherein in step (a3), the compound is reduced with
Pd/C.
It is to be understood that in case in step (a) a mixture of (II*)
and (II**) is provided, compound (IIa) also consists of a racemic
mixture, i.e. a mixture of the compounds (IIa*) and (IIa**)
##STR00177## R.sup.1a and R.sup.1
As mentioned above, R.sup.1a is H, PG.sup.1, R.sup.A or PG.sup.1a,
and wherein PG.sup.1a and PG.sup.2a are, independently of each
other, suitable protecting groups. Preferred protecting groups for
PG.sup.1a include, but are not limited to, carbamates, such as Boc
(t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc
(fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and
ethyl carbamates; trityl, benzyl, benzylidene, tosyl and the like;
cyclic imide derivatives, such as succinimide and phthalimide;
amides, such as formyl, (un)substituted acetyl, and benzoyl; and
trialkyl silyl groups, such as t-butyldimethylsilyl and
triisopropylsilyl. Particularly preferred amino-protecting groups
include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl and the
like. Most preferably, PG.sup.1a is a Boc group or a Cbz group,
more preferably Boc.
Preferred protecting groups for PG.sup.2a include, but are not
limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz
(carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc
(allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl,
benzylidene, tosyl and the like; cyclic imide derivatives, such as
succinimide and phthalimide; amides, such as formyl,
(un)substituted acetyl, and benzoyl; and trialkyl silyl groups,
such as t-butyldimethylsilyl and triisopropylsilyl. Particularly
preferred amino-protecting groups include Boc, Cbz (CBZ), Fmoc,
benzyl, acetyl, benzoyl, trityl and the like. Most preferably,
PG.sup.2a is a Boc group or a Cbz group, more preferably Cbz.
It is to be understood that R.sup.1a may be different from R.sup.1
or may be the same. Similarly, R.sup.2a may be different from
R.sup.2 or may be the same. In case R.sup.1 differs from R.sup.1a
or in case R.sup.2 differs from R.sup.2a or in case both R.sup.1a
and R.sup.2a differ from R.sup.1a and R.sup.2a, respectively, step
(a4) is carried out. In case R.sup.1 is equal to R.sup.1a and
R.sup.2 is equal to R.sup.2a, step (a4) is omitted.
It is thus to be understood that compound (IIa) may correspond to
compound (II), compound (IIa*) may correspond to (II*) and compound
(IIa**) may correspond to (II**) in case R.sup.1a is equal to
R.sup.1 and in case R.sup.2 is equal to R.sup.2a.
In case R.sup.1a is different from R.sup.1 and/or R.sup.2a is
different from R.sup.2, R.sup.1a and/or R.sup.2a is transformed in
step (a4) to R.sup.1 and R.sup.2, wherein this transformation may
be carried out in one or in multiple steps, to give compound (II)
or (II*), respectively. It is to be understood that in case (II)
corresponds to (IIa) or (II*) corresponds to (IIa**), step (a4) is
omitted.
In case in step (a) a compound having the structure (II*) is
provided as single (isolated) isomer, as mentioned above, step (a)
preferably comprises a chiral resolution of the compound of formula
(IIa) to give the compound of formula (IIa*), a chiral resolution
of the compound of formula (II) to give the compound of formula
(II*), and/or an enantioselective reduction in step (a3) to give
the compound of formula (IIa*) or (II*, respectively. Chiral
Resolution of the Compound of Formula (II)
As mentioned above, compound (II) may comprise a mixture of
compounds (II*) and (II'')
##STR00178##
In this case, a chiral resolution of (II) may be carried out. More
preferably, in case a chiral resolution is carried out at this
stage, R.sup.2 is H, and R.sup.1 is Boc. R.sup.E is preferably
methyl.
Preferably, the compound (II) contains of from 20 to 75% by weight
of the compound of formula (II*) based on the total weight of the
sum of (II*) and (II**). This mixture is then resolved by chiral
resolution to finally give, optionally after further steps, the
compound (II*).
Preferably, this is carried out by (i) adding a single stereoisomer
of a chiral acid and precipitating, preferably crystallizing, a
chiral acid salt (S) of compound (II), thereby obtaining a mixture
comprising the precipitated, preferably crystallized, tartaric acid
salt (S) and the solvent, (ii) preferably separating the
precipitated, preferably crystallized, chiral acid salt (S) of the
compound of formula (II) from the mixture obtained in (i), wherein
the chiral acid salt (S) contains at least 80% by weight of the
chiral acid salt of the compound of formula (II*) based on the
total weight of the chiral acid salt of the compound of formula
(II), (iii) converting the chiral acid salt (S) to the free
base.
Preferably, in step (i), upon addition of the chiral acid in a
suitable solvent, a chiral acid salt (S*) of at least part of the
compound of formula (II) is formed and at least part of this chiral
acid salt (S*) formed is precipitated, preferably crystallized,
thereby obtaining a mixture comprising the precipitated, preferably
crystallized, tartaric acid salt (S) and the solvent.
The chiral acid is preferably tartaric acid or a tartaric acid
derivative selected from the group consisting of Ditoluoyl tartaric
acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl
tartaric acid mono(dimethylamide) and a mixture of two or more
thereof, more preferably, the chiral acid is tartaric.
Step (i)
The compound of formula (II) employed in (i) contains of from 20 to
75% by weight, more preferably of from 40 to 60% by weight, of the
compound of formula (II*) based on the total weight of the sum of
(II*) and (II**).
In step (i), at least part of the compound of formula (II) is
transformed into the corresponding chiral acid salt, preferably
tartaric acid salt (S*). The chiral acid salt (S*) contains the
chiral acid salt of the compound of formula (II*), e.g. in an
amount in the range of from 1 to 80% by weight, such as in the
range of from 10 to 70% by weight, or in the range of from 30 to
60% by weigh, or in the range of from 45 to 55% by weight, based on
the total amount of the chiral acid salt (S*).
Subsequently, at least part of (S*) is precipitated, preferably
crystallized. This is preferably achieved by contacting (treating)
the compound of formula (II) in a suitable solvent with the chiral
acid. Thereby, a mixture comprising the crystallized chiral acid
salt (S) of the compound of formula (II*) and the solvent is
formed. As mentioned above, the precipitated, preferably
crystallized, tartaric acid salt (S) of the compound of formula
(II) contains at least 80% by weight of chiral acid salt of the
compound of formula (II*) based on the total weight of the chiral
acid salt of the compound of formula (II).
It is to be noted that the mixture obtained in step (i) may
comprise further compounds, in particular non crystalline forms of
the compound of formula (II) and salts thereof. Preferably, the
mixture obtained in (i) comprises non-crystalline forms of the
compound of formula (II**) and chiral acids salts thereof.
The chiral acid salt (S*) of the compound of formula (II) is
denoted to encompass all chiral acid salts of compound (II) formed
in step (i) including the chiral acid salt (S) which precipitates
as well as all chiral acid salts formed which remain dissolved
(S*--S). Thus, the chiral acid salt (S) may comprise a mixture of
chiral acid salt of compounds of formula (II*) and (II**).
As to the solvent used in step (i), any suitable organic solvent in
which the compound of formula (II) is sufficiently soluble may be
used. In particular, the solvent is selected from the group
consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE,
CH.sub.2Cl.sub.2, ethyl acetate, acetone, isopropanol, methanol,
water, formic acid ethyl ester, isopropyl acetate, propyl acetate,
butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane,
methylisobutylketone, toluene, hexane, cyclohexane, heptane and
mixtures of two or more thereof. More preferably, the solvent
comprises methylisobutylketone, preferably is
methylisobutylketone.
It is to be understood that in step (i) a further solvent may be
added in order to precipitate, preferably crystallize, the chiral
acid salt (S). In this case, the mixture obtained in (i) preferably
additionally comprises the further solvent.
This further solvent may be added prior to, together with or after
the addition of the chiral acid to the compound of formula (II).
According to a preferred embodiment, the compound of formula (II)
is dissolved in the suitable solvent mentioned above and a mixture,
preferably a solution of the chiral acid, in a further solvent is
added to the solution, wherein the further solvent and the suitable
solvent may be the same or may be different.
In particular, the further solvent is selected from the group
consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE,
CH.sub.2Cl.sub.2, ethyl acetate, acetone, isopropanol, methanol,
water, formic acid ethyl ester, isopropyl acetate, propyl acetate,
butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane,
methylisobutylketone, toluene, hexane, cyclohexane, heptane and
mixtures of two or more thereof. More preferably, the suitable
solvent and the further solvent are the same, in particular, they
both comprise methylisobutylketone, preferably both are
methylisobutylketone.
Thus, the present invention also relates to a process for the
preparation of a chiral acid salt (S) of a compound of formula
(II), as described above, and a chiral acid salt (S) of compound of
formula (II), obtained or obtainable by said process, wherein step
(i) comprises dissolving the compound of formula (II) in the
suitable solvent and adding a solution of the chiral acid dissolved
in a further solvent to the solution, wherein the further solvent
and the suitable solvent are preferably the same, more preferably
methylisobutylketone.
Preferably, the compound of formula (II) is dissolved in the
suitable solvent and the mixture is heated to a temperature in the
range of from 30 to 80.degree. C., more preferably to a temperature
in the range of from 30 to 60.degree. C., more preferably to a
temperature in the range of from 30 to 50.degree. C., more
preferably to a temperature in the range of from 30 to 40.degree.
C., prior to the addition of the tartaric acid. During the heating
step, the temperature may be varied, constantly or stepwise, or
held essentially constant. Preferably, the mixture is heated until
a clear solution of the compound of formula (II) in the suitable
solvent is obtained. Optionally, the mixture is afterwards cooled
to room temperature.
The precipitation, preferably the crystallizing, in step (i) is
preferably carried out at a temperature in the range of from 0 to
60.degree. C., wherein the temperature is preferably continuously
or stepwise decreased during step (i). The chiral acid may thus
e.g. be added to a solution of the compound of formula (II) in the
suitable solvent which has been previously heated or which has been
previously heated and afterwards cooled to a specific temperature
or which has not been previously heated.
After the addition of the chiral acid, and optionally the further
solvent, the mixture may again be heated or alternatively be cooled
or the temperature may be held constant. Preferably, the mixture is
cooled to a temperature in the range of from 0 to 50.degree. C.,
more preferably to a temperature in the range of from 0 to
40.degree. C., more preferably to a temperature in the range of
from 10 to 30.degree. C.
Preferably, the mixture obtained in step (i) consists of the chiral
acid salt (S), optionally the unreacted chiral acid, optionally the
unreacted compound of formula (II), precipitated chiral acid salts
(salt (S*) minus the amount of precipitated chiral acid salt (S)),
the suitable solvent and optionally the further suitable
solvent.
Step (ii)
In the optional step (ii) of the process of the invention, the
chiral acid salt (S) is separated from the mixture obtained in step
(i).
The separation may be carried out by any suitable method known to
those skilled in the art. Preferably, the separating in step (ii)
is carried out by centrifugation or filtration, preferably
filtration.
It is to be understood that the separated salt may be subjected to
a further treatment such as an after-treatment such as a
purification step and/or lyophilization.
Preferably, the obtained chiral acid salt (S) of the compound
formula (II) contains at least 90% by weight, more preferably at
least 95% by weight, more preferably at least 96% by weight, more
preferably at least 97% by weight, more preferably at least 98% by
weight, more preferably at least 99% by weight, of the tartaric
salt of the compound of formula (II*), based on the total weight of
chiral acid salt of the compound of formula (II), i.e. based on the
sum of (II**) and (II*). More preferably, the chiral acid salt (S)
of the compound of formula (II) is the isolated chiral acid salt of
the compound of formula (II*).
The term "isolated chiral acid salt of the compound of formula
(II*)" in this context is denoted to mean that the salt of the
compound of formula (II*) comprises less than 1% by weight of the
salt of compound (II**), preferably less than 0.5% by weight, more
preferably less than 0.1% by weight, more preferably less than
0.05% by weight, more preferably less than 0.01% by weight, more
preferably essentially no, more preferably no compound of formula
(II**) based on the total weight of the salts of (II*) and
(II**).
Chiral Resolution of the Compound of Formula (IIa*)
Alternatively, in case (II) differs from (IIa), also a chiral
resolution of compound (IIa) may be carried out. As mentioned
above, compound (II) may comprise a mixture of compounds (IIa*) and
(IIa**)
##STR00179##
The chiral resolution of compound (IIa) is carried out as discloses
above in connection with the chiral resolution of compound of
formula (II).
Enantioselective Reduction
According to a further preferred embodiment, in step (a3), the
compound is stereoselectively reduced to give a compound of formula
(IIa*)
##STR00180##
In this case, preferably a chiral catalyst, i.e. a metal catalyst
comprising a chiral ligand is employed. As mentioned above,
preferably a metal catalyst and hydrogen is used. The metal
catalyst is preferably selected from the group consisting of a
catalyst comprising Pd, Fe, Ir, Rh and mixtures of two or more
thereof. In case of a stereoselective reduction, the metal catalyst
is preferably selected from the group consisting of a catalyst
comprising Pd, Fe, Ir, Rh, and mixtures of two or more thereof.
Preferably, the catalyst comprises Fe and/or Rh.
The reaction is preferably carried out at a hydrogen pressure in
the range of from 1 to 25 bar, more preferably, 2.5 to 10 bar.
During the reaction, the pressure may be varied or held essentially
constant.
Preferably, the reaction is carried out at a temperature in the
range of from 10 to 100.degree. C., more preferably in the range of
from 20 to 60.degree. C., more preferably at 25 to 40 C. During the
reaction, the temperature may be varied or held essentially
constant.
The reaction may be carried out in any suitable solvent known to
those skilled in the art. Preferably, the cyclization reaction is
carried out in an organic solvent, more preferably in a solvent
selected from the group consisting of methanol, ethanol,
trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol,
ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol,
tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether,
diethylether, diisopropylether, toluene, acetonitrile and mixtures
of two or more thereof. Preferably, the solvent is methanol or
TFE.
Preferably in compound (IIa), R.sup.1 is Boc and R.sup.2 is H.
Step (a1)
In step (a1), a compound of formula (III) is reacted with a
compound of formula (IV) to give the compound of formula (V).
Preferably, step (a1) is carried out at a temperature in the range
of from 0 to 80.degree. C., more preferably in the range of from 10
to 50.degree. C., more preferably in the range of from 20 to
35.degree. C. During the reaction, the temperature may be varied or
held essentially constant.
Preferably, an organic solvent is used in step (a1), more
preferably in a solvent selected from the group consisting of
methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF,
DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol,
s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran,
methyltertbutylether, diethylether, diisopropylether, toluene,
acetonitrile and mixtures of two or more thereof. Most preferably,
the reaction is carried out in dichloromethane.
Preferably, (a1) is carried out in the presence of a catalysing
agent, such as a dehydrating reagent or an acidic catalyst. The
term "dehydrating agent" is denoted to mean an agent which removes
water from the reagents such as by absorption. Such dehydrating
agents are known to those skilled in the art. Preferably, the
catalysing agent is SiO.sub.2 or a molecular sieve or a mixture
thereof. More preferably, the catalysing agent SiO.sub.2.
Step (a2)
Preferably, the reaction mixture obtained in step (a1) is subjected
to a suitable work-up in step (a2), such as an isolation of the
respective compound of formula (V). Such working up may comprise
one or more stages wherein preferably at least one stage comprises
a purification step, such as an extraction and/or a precipitation
and/or filtration and/or chromatography or the like. Preferably,
the reaction mixture is filtered to remove the SiO.sub.2 and the
solvent is removed, such as under reduced pressure.
More preferably, compound (V) is further purified, e.g. by
distillation.
Step (a4)
As mentioned above, R.sup.1a may be different from R.sup.1 and/or
R.sup.2a may be different from R.sup.2. In particular, the
following embodiments are mentioned by way of example:
TABLE-US-00002 ##STR00181## ##STR00182## Entry R.sup.1a R.sup.2a
R.sup.1 R.sup.2 1 PG.sup.1 PG.sup.2 H PG.sup.2 2 PG.sup.1 H H
PG.sup.2 3 PG.sup.1 H H ##STR00183## 4 ##STR00184## H ##STR00185##
PG.sup.2 5 ##STR00186## H ##STR00187## ##STR00188## 6 H
##STR00189## ##STR00190## ##STR00191##
In the above mentioned table PG.sup.1 is preferably Boc and
PG.sup.2 is preferably Cbz.
In case R.sup.1 differs from R.sup.1a or in case R.sup.2 differs
from R.sup.2a or in case both R.sup.1a and R.sup.2a differ from
R.sup.1a and R.sup.2a, respectively, step (a4) is carried out.
Depending on the respective groups to be replaced, step (a4)
comprises one or multiple step, such a deprotection step and/or a
protection step and/or a coupling step with a compound of
formula
##STR00192## and/or a coupling step with a compound of formula
##STR00193## to give the compound of formula (II).
According to a preferred embodiment, step (a) according to the
invention e.g. comprises (a1) reacting a compound of formula
(III)
##STR00194## with a compound of formula (IV)
##STR00195## to give a compound of formula (V)
##STR00196## wherein R.sup.1a is PG.sup.1 and wherein R.sup.2a is
H, and PG.sup.1a is a suitable protecting group, preferably a Boc
group, (a2) optionally purifying the compound of formula (V), (a3)
reducing the compound of formula (V) to give a compound of formula
(IIa), wherein R.sup.1a is PG.sup.1 and wherein R.sup.2a is H (a4)
replacing R.sup.2a with
##STR00197## by reacting a compound of formula (IIa) with a
compound of formula (XI)
##STR00198## wherein E is --COOH or a reactive carboxy group, and
replacing R.sup.1a with H by removing the protecting group
PG.sup.1.
Further, the present invention also relates to the preparation of a
compound of formula (IIa) and to a compound (IIa) obtained or
obtainable by said method, the method comprising (a1) reacting a
compound of formula (III)
##STR00199## with a compound of formula (IV)
##STR00200## to give a compound of formula (V)
##STR00201## wherein R.sup.1a is PG.sup.1 and wherein R.sup.2a is
H, and PG.sup.1a is a suitable protecting group, preferably a Boc
group, (a2) optionally purifying the compound of formula (V), (a3)
reducing the compound of formula (V) to give a compound of formula
(IIa), wherein R.sup.1a is PG.sup.1 and wherein R.sup.2a is H.
Methods for attaching and removing of a protecting group are known
to those skilled in the art and depend on the respective protecting
group employed.
Representative protecting groups for amino groups are well known to
those skilled in the art and methods for attaching them to amino
groups as well as removing them are described, for example, in T.
W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis,
Third Edition, Wiley, N.Y., 1999, and references cited therein.
In case, the protecting group is a Boc group, the removal is
preferably carried out under acidic conditions. More preferably,
the removal is carried out with HCl or TFA. The removal of such
protecting groups may be carried out in any suitable solvent known
to those skilled in the art. Preferably, the reaction is carried
out in an organic solvent, more preferably in a solvent selected
from the group consisting of methanol, ethanol, trifluoroethanol
(TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol,
propanol, isopropanol, butanol, s-butanol, t-butanol,
tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether,
diethylether, diisopropylether, toluene, acetonitrile and mixtures
of two or more thereof. Preferably, the removal is carried out at a
temperature in the range of from 0 to 40.degree. C., more
preferably in the range of from 10 to 30.degree. C., more
preferably at room temperature. During the reaction, the
temperature may be varied or held essentially constant.
In case, the protecting group is a Cbz group, the removal is
preferably carried out under reductive conditions. More preferably,
the removal is carried out with hydrogen and a metal catalyst,
preferably a palladium catalyst, more preferably the protecting
group is removed with Pd/C. The removal of such a protecting group
may be carried out in any suitable solvent known to those skilled
in the art. Preferably, the reaction is carried out in an organic
solvent, more preferably in a solvent selected from the group
consisting of methanol, ethanol, trifluoroethanol (TFE),
dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol,
isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran,
2-methyltetrahydrofuran, methyltertbutylether, diethylether,
diisopropylether, toluene, acetonitrile and mixtures of two or more
thereof and mixtures of two or more thereof. Preferably, the
removal is carried out at a temperature in the range of from 0 to
60.degree. C., more preferably in the range of from 10 to
50.degree. C., more preferably at room temperature. During the
reaction, the temperature may be varied or held essentially
constant. In case hydrogen is used, the reaction is preferably
carried out at a pressure in the range of from 1 to 3 bar, more
preferably, 1.5 to 2.5 bar.
In case in step (a4) the respective compound is reacted, i.e.
coupled, with a compound of formula (XI), wherein E is --COOH or a
reactive carboxy group, the coupling is preferably carried out in
the presence of a suitable base, preferably an organic base, most
preferably an amino group comprising base, most preferably a base
selected from the group consisting of diisopropylamine (DIEA),
triethylamine (TEA), N-methylmorpholine, N-methyl-imidazole,
1,4-diazabicyclo[2.2.2]octane (DABCO), N-methylpiperidine,
N-methylpyrrolidine, 2,6-lutidine, collidine, pyridine,
4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
As regards the reaction conditions used in this coupling step,
preferably, the reaction is carried out in an organic solvent, such
as N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO),
acetonitrile, acetone, dimethyl acetamide (DMA), dimethyl formamide
(DMF), formamide, tetrahydrofuran (THF), 1,4-dioxane, diethyl
ether, tert.-butyl methyl ether (MTBE), dichloromethane (DCM),
chloroform, tetrachloromethane and mixtures of two or more thereof.
More preferably, the reaction is carried out in
dichloromethane.
The temperature of the coupling reaction is preferably in the range
of from 0 to 100 C, more preferably in the range of from 5 to
50.degree. C., and especially preferably in the range of from 15 to
30.degree. C. During the course of the reaction, the temperature
may be varied, preferably in the above given ranges, or held
essentially constant.
With respect to preferred groups E, reference is made to the
respective details given above with respect to step (d1) which
equally apply.
Compound A
The present invention is further directed to a compound of formula
(A) of structure
##STR00202## wherein n is 1 or 0.
Thus the compound (A) has, e.g., the structure (Ia) or (Ib)
##STR00203## Residue R.sup.1:
Regarding R.sup.1, R.sup.1 is selected from the group consisting of
H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00204## wherein PG.sup.1 is a suitable protecting group.
Thus, the compound of formula (A) has, e.g., a structure selected
from the group consisting of
##STR00205## i.e. a structure selected from the group consisting
of
##STR00206## wherein at each occurrence R.sup.2 is as defined above
and wherein preferably in formula (Ia-1), (Ia-4), (Ia-6) R.sup.2 is
not H and wherein preferably in (Ia-6) R.sup.2 is not
##STR00207##
Preferably, the structures are selected from the group consisting
of
##STR00208## wherein in formula (Ia-1) R.sup.2 is not H.
The term "suitable protecting group" as used herein is denoted to
encompass any amino protecting group. The term "protecting group"
as such refers to a chemical moiety that can be selectively
attached to and removed from a particular chemically reactive
functional group in a molecule to prevent it from participating in
undesired chemical reactions. The protecting group will vary
depending on reaction conditions to be employed and the presence of
additional reactive or protecting groups in the molecule. It is
understood that the term "amino protecting group" is a chemical
moiety being attached to a former amino group. After removal of the
protecting group, the free amine is regained. Representative
protecting groups for amino groups are well known to those skilled
in the art and are described, for example, in T. W. Greene and G.
M. Wuts, Protecting Groups in Organic Synthesis, Third Edition,
Wiley, N.Y., 1999, and references cited therein.
An "amino-protecting group" preferably includes both acyclic as
well as cyclic protecting groups. A "cyclic protecting group" is a
group which, together with the N to which it is bound, forms a
cyclic group. Preferred protecting groups for PG.sup.1 include, but
are not limited to, carbamates, such as Boc (t-butyloxycarbonyl,
Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc
(allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl,
benzylidene, tosyl, PNZ, trifluoroacetate, phtalimide and the like;
cyclic imide derivatives, such as succinimide and phthalimide;
amides, such as formyl, (un)substituted acetyl, and benzoyl; and
trialkyl silyl groups, such as t-butyldimethylsilyl and
triisopropylsilyl. Particularly preferred amino-protecting groups
include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl, Cbz, PNZ,
Alloc, Trifluoroacetate, Phthalimide and the like. Most preferably,
PG.sup.1 is wherein PG.sup.2 is selected from the group consisting
of Benzyl, t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc,
Trifluoroacetate and Phthalimide, more preferably PG.sup.1 is a Boc
group or a Cbz group, more preferably Boc.
Thus, compound A is preferably selected from the group consisting
of
##STR00209## wherein at each occurrence R.sup.2 is as defined above
and wherein preferably in formula (Ia-1), (Ia-4), (Ia-6) R.sup.2 is
not H and wherein preferably in (Ia-6) R.sup.2 is not
##STR00210##
More preferably, compound A is selected from the group consisting
of
##STR00211## wherein in formula (Ia-1) R.sup.2 is not H.
Preferably R.sup.1 is selected from the group consisting of H,
##STR00212##
Most preferably R.sup.1 is H.
Residue R.sup.2:
Regarding R.sup.2, R.sup.2 is selected from the group consisting of
H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00213## and wherein PG.sup.2 is a suitable protecting group,
and wherein n is 0 or 1.
Thus, the compound of formula (A) has, e.g., a structure selected
from the group consisting of
##STR00214## i.e. a structure selected from the group consisting
of
##STR00215## wherein in (Ia-a), in (Ia-b), in (Ia-e) R.sup.1 is not
H, wherein in (Ia-e) R.sup.1 is not
##STR00216##
PG.sup.2 is a suitable protecting group as defined above in
connection with PG.sup.1. Preferred protecting groups for PG.sup.2
include, but are not limited to, carbamates, such as Boc
(t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc
(fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and
ethyl carbamates; trityl, benzyl, benzylidene, tosyl, PNZ,
trifluoroacetate, phtalimideand the like; cyclic imide derivatives,
such as succinimide and phthalimide; amides, such as formyl,
(un)substituted acetyl, and benzoyl; and trialkyl silyl groups,
such as t-butyldimethylsilyl and triisopropylsilyl. Particularly
preferred amino-protecting groups include Boc, Cbz, Fmoc, benzyl,
acetyl, benzoyl, trityl, Cbz, PNZ, Alloc, Trifluoroacetate,
Phthalimide and the like. Most preferably, PG.sup.1 is wherein
PG.sup.2 is selected from the group consisting of Benzyl,
t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc, Trifluoroacetate and
Phthalimide, more preferably PG.sup.2 is a Boc group or a Cbz
group, more preferably Cbz.
Thus, compound A is preferably selected from the group consisting
of
##STR00217## wherein in (Ia-a), in (Ia-b), in (Ia-e) R.sup.1 is not
H, wherein in (Ia-e) R.sup.1 is not
##STR00218##
More preferably, compound A is selected from the group consisting
of
##STR00219## wherein in (Ia-a) R.sup.1 is not H.
It is to be understood that in case R.sup.1 and R.sup.2 are both
protecting groups, PG.sup.1 and PG.sup.2 preferably differ from
each other. In this case, R.sup.1 and R.sup.2 are preferably
orthogonal protecting groups as described above.
Compound A*
The present invention is further directed to compound of formula
(A) of structure
##STR00220## wherein n is 1 or 0.
Thus the compound (A) has, e.g., the structure (Ia) or (Ib)
##STR00221## Residue R.sup.1:
Regarding R.sup.1, R.sup.1 is selected from the group consisting of
H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00222## wherein PG.sup.1 is a suitable protecting group.
Thus, the compound of formula (A) has, e.g., a structure selected
from the group consisting of
##STR00223## i.e. a structure selected from the group consisting
of
##STR00224## wherein at each occurrence R.sup.2 is as defined above
and wherein preferably in formula (Ia*-1), (Ia*-4), (Ia*-6) R.sup.2
is not H and wherein preferably in (Ia*-6) R.sup.2 is not
##STR00225##
Preferably, the structures are selected from the group consisting
of
##STR00226## wherein in formula (Ia*-1) R.sup.2 is not H.
Compound (A) is preferably selected from the group consisting
of
##STR00227## wherein at each occurrence R.sup.2 is as defined above
and wherein preferably in formula (Ia*-1), (Ia*-4), (Ia*-6) R.sup.2
is not H and wherein preferably in (Ia*-6) R.sup.2 is not
##STR00228##
More preferably compound A is selected from the group consisting
of
##STR00229## wherein in formula (Ia*-1) R.sup.2 is not H.
Preferably, R.sup.1 is selected from the group consisting of H,
##STR00230## most preferably R.sup.1 is H. Residue R.sup.2:
Regarding R.sup.2, R.sup.2 is selected from the group consisting of
H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00231## and wherein PG.sup.2 is a suitable protecting group,
and wherein n is 0 or 1.
Thus, the compound of formula (A) has, e.g., a structure selected
from the group consisting of
##STR00232## i.e. a structure selected from the group consisting
of
##STR00233## wherein in (Ia*-a), in (Ia*-b), in (Ia*-e) R.sup.1 is
not H, wherein in (Ia*-e) R.sup.1 is not
##STR00234##
PG.sup.2 is a suitable protecting group as defined above in
connection with PG.sup.1. Preferred protecting groups for PG.sup.2
include, but are not limited to, carbamates, such as Boc
(t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc
(fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and
ethyl carbamates; trityl, benzyl, benzylidene, tosyl, PNZ,
trifluoroacetate, phtalimideand the like; cyclic imide derivatives,
such as succinimide and phthalimide; amides, such as formyl,
(un)substituted acetyl, and benzoyl; and trialkyl silyl groups,
such as t-butyldimethylsilyl and triisopropylsilyl. Particularly
preferred amino-protecting groups include Boc, Cbz, Fmoc, benzyl,
acetyl, benzoyl, trityl, Cbz, PNZ, Alloc, Trifluoroacetate,
Phthalimide and the like. Most preferably, PG.sup.1 is wherein
PG.sup.2 is selected from the group consisting of Benzyl,
t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc, Trifluoroacetate and
Phthalimide, more preferably PG.sup.2 is a Boc group or a Cbz
group, more preferably Cbz.
Thus, compound A is preferably selected from the group consisting
of
##STR00235## wherein in (Ia*-a), in (Ia*-b), in (Ia*-e) R.sup.1 is
not H, wherein in (Ia*-e) R.sup.1 is not
##STR00236##
More preferably, compound A is selected from the group consisting
of
##STR00237## wherein in (Ia*-a) R.sup.1 is not H.
It is to be understood that in case R.sup.1 and R.sup.2 are both
protecting groups, PG.sup.1 and PG.sup.2 preferably differ from
each other. In this case, R.sup.1 and R.sup.2 are preferably
orthogonal protecting groups as described above.
Preferably, compound (A) and compound (A*) e.g. have as structure
selected from the structure shown in the table below:
TABLE-US-00003 ##STR00238## Struc- ture Num- ber n R.sup.1 R.sup.2
2 1 H Cbz 3 1 H ##STR00239## 4 1 Boc H 5 1 Boc Cbz 6 1 Boc
##STR00240## 7 1 ##STR00241## H 8 1 ##STR00242## Cbz 9 1
##STR00243## ##STR00244## 10 1 ##STR00245## H 11 1 ##STR00246## Cbz
12 1 ##STR00247## ##STR00248## 14 0 H Cbz 16 0 Boc H 17 0 Boc Cbz
19 0 Boc ##STR00249## 20 0 ##STR00250## Cbz 22 0 ##STR00251## H 23
0 ##STR00252## Cbz 24 0 ##STR00253## ##STR00254##
Further, the present invention is directed to a crystalline form
(A) of compound of formula
##STR00255## wherein R.sup.1 is H, i.e. to a crystalline compound
of formula
##STR00256##
Crystalline form (A) has an X-ray powder diffraction pattern
comprising a peak at 2-theta angle of approximately
12.4.degree..+-.0.2.degree., more preferably has an X-ray powder
diffraction pattern comprising peaks at 2-theta angles of
approximately 4.8.+-.0.2.degree., 12.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 19.9.degree..+-.0.2.degree. and
20.8.degree..+-.0.2.degree. and/or at approximately
7.7.+-.0.2.degree., 11.4.degree..+-.0.2.degree.,
12.4.degree..+-.0.2.degree., 16.2.degree..+-.0.2.degree. and
18.1.degree..+-.0.2.degree., more preferably, at approximately
4.8.+-.0.2.degree., 12.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 19.9.degree..+-.0.2.degree. and
20.8.degree..+-.0.2.degree., wherein the X-ray powder diffraction
pattern is measured at a temperature in the range of from 15 to
25.degree. C. with Cu-K.alpha..sub.1,2 radiation having a
wavelength of 0.15419 nm.
Alternatively crystalline form (A) has an X-ray powder diffraction
pattern comprising a peak at 2-theta angle of approximately
12.4.degree..+-.0.2.degree., more preferably has an X-ray powder
diffraction pattern comprising peaks at 2-theta angles of
approximately 4.8.+-.0.2.degree., 12.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 19.9.degree..+-.0.2.degree. and
20.8.degree..+-.0.2. The X-ray preferably further comprises peaks
at one or more than one or all of 2-theta angles of
21.6.degree..+-.0.2.degree., 22.6.degree..+-.0.2.degree.
22.9.degree..+-.0.2 and 27.8.degree..+-.0.2.degree.. The X-ray
powder diffraction pattern is measured at a temperature in the
range of from 15 to 25.degree. C. with Cu-K.alpha..sub.1,2
radiation having a wavelength of 0.15419 nm.
An XRPD of crystalline form (A) of compound (VIIb-H) is depicted in
FIG. 3.
A peak listing of the XRPD of crystalline form (A) of compound
(VIIb-H) is presented in Table 1
TABLE-US-00004 TABLE 1 No. Pos. [.degree.2Th. Rel. Int. [%] 1 2.3 4
2 4.8 44 3 9.6 3 4 12.4 88 5 14.2 43 6 14.4 19 7 17.1 5 8 17.9 6 9
18.1 6 10 19.2 7 11 19.6 16 12 19.9 27 13 20.8 100 14 21.6 24 15
22.6 25 16 22.9 19 17 24.2 1 18 25.0 7 19 25.9 6 20 26.5 8 21 26.7
9 22 27.5 5 23 27.8 20 24 28.4 6 25 28.7 7 26 29.3 2 27 30.1 6 28
31.5 2 29 32.1 2 30 33.1 2 31 33.9 2 32 35.0 5 33 35.5 2 34 36.4 1
35 37.3 2 36 38.4 4 37 39.3 2
The present invention is further directed to compound of formula
(VIIb*), wherein R.sup.1 is H
##STR00257## i.e. to a compound of formula (VIIb*-H)
##STR00258##
Preferably the compound of formula (VIIb*-H) is crystalline. More
preferably, the crystalline compound of formula (VIIb*-H) is the
crystalline form (I). Crystalline form (I) has an X-ray powder
diffraction pattern comprising a peak at 2-theta angle of
approximately 11.3.degree..+-.0.2.degree., more preferably has an
X-ray powder diffraction pattern comprising peaks at 2-theta angles
of 11.3.+-.0.2.degree., 12.3.degree..+-.0.2.degree.,
13.3.degree..+-.0.2.degree., 16.0.degree..+-.0.2.degree.
20.00.+-.0.2.degree.. The X-ray powder diffraction pattern of
crystalline form (I) preferably further comprises peaks at 2-theta
angles of 16.5.+-.0.2.degree., 18.3.degree..+-.0.2.degree.,
20.1.degree..+-.0.2.degree., 22.7.degree..+-.0.2.degree., wherein
the X-ray powder diffraction pattern is measured at a temperature
in the range of from 15 to 25.degree. C. with Cu-K.alpha..sub.1,2
radiation having a wavelength of 0.15419 nm.
An XRPD of crystalline form (I) of compound (VIIb*-H) is depicted
in FIG. 4.
A peak listing of the XRPD of form (I) is presented in Table 2.
TABLE-US-00005 TABLE 2 No. Pos. [.degree.2Th. Rel. Int. [%] 1 11.3
100 2 12.3 93 3 13.3 59 4 16.0 39 5 16.5 18 6 16.9 9 7 17.1 7 8
18.3 32 9 19.1 10 10 20.0 83 11 20.1 45 12 22.0 17 13 22.1 15 14
22.4 16 15 22.7 46 16 24.1 11 17 24.8 7 18 25.7 16 19 26.4 3 20
26.7 9 21 27.0 11 22 27.7 6 23 27.8 10 24 28.1 21 25 28.5 4 26 30.3
1 27 30.8 1 28 31.4 1 29 32.5 3 30 32.8 10 31 34.0 3 32 35.3 3 33
36.2 1 34 37.1 2 35 37.9 3 36 39.1 1
Regarding form (I), it is prepared by crystallization of compound
of formula (VIIb*-H) in a solvent, wherein the solvent is
preferably selected from the group consisting of ethyl acetate,
methanol, CH.sub.2Cl.sub.2, acetonitrile, isopropyl acetate,
acetone, ethanol, isopropanol, toluene, butanol, isobutanol,
t-butanol, tetrahydrofuran, methyltetrahydrofuran, cyclohexane and
mixture thereof. More preferably the solvent is ethyl acetate.
Regarding the temperature of the crystallization process there is
no specific limitation provided that the crystalline form (I) is
obtained. Preferably, the temperature is in the range of from -30
to 70.degree. C., more preferably 10 to 50.degree. C., even more
preferably 10 to 30.degree. C.
The present invention is further directed to the sulphate salt of
the compound of formula (VIIb-H) and (VIIb*-H), more preferably of
formula (VIIb*-H), the sulphate salt having formulae
##STR00259##
Regarding the sulphate salt of formula (VIIb-S) or formula
(VIIb*-S), it is prepared by any suitable method for preparing
sulphate salt. In an embodiment, the sulphate salt of formula
(VIIb-S) or of formula (VIIb*-S), it is prepared by adding
H.sub.2SO.sub.4 to a solution comprising the compound of formula
(VIIb-H) or of formula (VIIb*-H). Preferably the solvent of the
solution is selected from the group consisting of ethyl acetate,
methanol, CH.sub.2Cl.sub.2, acetonitrile, isopropyl acetate,
acetone, ethanol, isopropanol, toluene, butanol, isobutanol,
t-butanol, tetrahydrofuran, methyltetrahydrofuran, cyclohexane and
mixture thereof, wherein the solvent is preferably selected from
the group consisting of ethyl acetate, methanol, CH.sub.2Cl.sub.2
and mixture thereof.
Preferably the sulphate salt of formula (VIIb-S) and of formula
(VIIb*-S) is crystalline.
In an embodiment, the crystalline sulphate of formula (VIIb*-S) is
in the crystalline form (I-S). Crystalline form (I-S) has an X-ray
powder diffraction pattern comprising a peak at 2-theta angle of
approximately 14.3.degree..+-.0.2.degree., more preferably has an
X-ray powder diffraction pattern comprising peaks at 2-theta angles
of 7.8.+-.0.2.degree., 8.6.degree..+-.0.2.degree.,
9.1.degree..+-.0.2.degree., 14.3.degree..+-.0.2,
17.4.degree..+-.0.2.degree., 19.7.degree..+-.0.2.degree., wherein
the X-ray powder diffraction pattern is measured at a temperature
in the range of from 15 to 25.degree. C. with Cu-K.alpha..sub.1,2
radiation having a wavelength of 0.15419 nm.
Preferably the X-ray powder diffraction pattern of crystalline form
(I-S) further comprises peaks at 2-theta angles of
14.7.+-.0.2.degree., 21.7.degree..+-.0.2.degree.,
24.0.degree..+-.0.2.degree..
A peak listing of the XRPD of form (I-S) is presented in Table
3.
TABLE-US-00006 TABLE 3 No. Pos. [.degree.2Th. Rel. Int. [%] 1 7.8
17 2 8.6 72 3 9.1 24 4 13.8 9 5 14.3 79 6 14.7 30 7 15.0 12 8 15.9
23 9 17.4 77 10 18.2 3 11 18.9 1 12 19.7 100 13 19.9 27 14 20.7 4
15 21.1 17 16 21.7 30 17 23.1 5 18 24.0 57 19 24.5 12 20 24.9 19 21
25.3 26 22 25.5 10 23 25.7 8 24 26.2 8 25 26.5 5 26 26.9 2 27 27.4
2 28 27.8 13 29 28.2 4 30 28.8 22 31 29.8 6 32 30.2 12 33 30.7 2 34
31.6 1 35 32.2 5 36 32.6 4 37 33.7 3 38 34.7 2 39 34.9 2 40 35.8 2
41 36.8 1 42 37.3 2 43 38.1 2 44 39.0 2
An XRPD of crystalline form (I-S) is disclosed in FIG. 5.
Regarding the crystalline form (I-S) of the compound of formula
(VIIb*-S) it is prepared by adding H.sub.2SO.sub.4 to a solution
comprising the compound of formula (VIIb*). Preferably the solvent
of the solution is selected from the group consisting of ethyl
acetate, methanol, CH.sub.2Cl.sub.2, acetonitrile, isopropyl
acetate, acetone, ethanol, isopropanol, toluene, butanol,
isobutanol, t-butanol, tetrahydrofuran, methyltetrahydrofuran,
cyclohexane and mixture thereof, wherein the solvent is preferably
selected from the group consisting of ethyl acetate, methanol,
CH.sub.2Cl.sub.2 and a mixture thereof.
Regarding form (I-S), it is prepared by crystallization in a
solvent of the sulphate salt of formula (VIIb*-S), wherein the
solvent is preferably selected from the group consisting of ethyl
acetate, methanol, CH.sub.2Cl.sub.2 and a mixture thereof.
Regarding the temperature of the crystallization process there is
no specific limitation provided that the crystalline form (I-S) is
obtained. Preferably the temperature is in the range of from -30 to
70.degree. C., more preferably in the range of from 10 to
50.degree. C., even more in the range of from 10 to 30.degree.
C.
The present invention is further directed to the hydrochloride salt
of the compound of formula (VIIb) or of formula (VIIb*) having
formulae (VIIb-Cl) and (VIIb*-Cl)
##STR00260##
Regarding the hydrochloride salt of formula (VIIb-Cl) or formula
(VIIb*-Cl), it is prepared by any suitable method for preparing
hydrochloride salt.
Preferably, the hydrochloride salt of formula (VIIb-Cl) or of
formula (VIIb*-Cl) is crystalline.
In an embodiment, the crystalline hydrochloride salt of formula
(VIIb*-Cl) is the crystalline form (I-Cl). Crystalline form (I-Cl)
has an X-ray powder diffraction pattern comprising a peak at
2-theta angle of approximately 15.2.degree..+-.0.2.degree., more
preferably has an X-ray powder diffraction pattern comprising peaks
at 2-theta angles of 10.5.+-.0.2.degree.,
11.5.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree.,
16.6.degree..+-.0.2, 22.4.degree..+-.0.2.degree., the X-ray powder
diffraction pattern is measured at a temperature in the range of
from 15 to 25.degree. C. with Cu-K.alpha..sub.1,2 radiation having
a wavelength of 0.15419 nm.
The X-ray powder diffraction pattern of form (I-Cl) preferably
further comprises peaks at 2-theta angles of 18.5..+-.0.2.degree.,
23.9.degree..+-.0.2.degree..
A peak listing of the XRPD of form (I-Cl) is presented in Table
4.
TABLE-US-00007 TABLE 4 No. Pos. [.degree.2Th. Rel. Int. [%] 1 9.6 7
2 10.5 68 3 11.5 15 4 12.0 11 5 12.9 15 6 14.8 12 7 15.2 100 8 16.3
15 9 16.6 36 10 17.3 2 11 17.5 9 12 18.3 4 13 18.5 18 14 18.9 7 15
19.4 12 16 19.5 10 17 19.8 4 18 21.1 10 19 21.2 15 20 21.4 8 21
22.4 76 22 23.6 25 23 23.9 28 24 24.4 2 25 25.2 20 26 25.9 7 27
26.1 10 28 26.7 4 29 27.3 6 30 27.8 5 31 28.7 4 32 29.2 5 33 29.9 5
34 30.5 6 35 31.3 3 36 31.5 5 37 31.8 2 38 32.4 4 39 32.7 5 40 33.6
1 41 34.1 2 42 35.1 4 43 35.9 3 44 36.3 4 45 37.0 1 46 37.9 1 47
38.3 4 48 39.0 2 49 39.6 3
An XRPD of crystalline form (I-Cl) is disclosed in FIG. 6.
Regarding the hydrochloride salt of formula (VIIb-Cl) or formula
(VIIb*-Cl) it is prepared by adding HCl, preferably methanolic HCl
to a solution comprising the compound of formula (VIIb) or of
formula (VIIb*).
Regarding crystalline form (I-Cl), it is prepared by
crystallization in a solvent of the hydrochloride salt of formula
(VIIb*-Cl), wherein the solvent is preferably selected from the
group consisting of ethyl acetate, methanol, CH.sub.2Cl.sub.2,
acetonitrile, isopropyl acetate, acetone, ethanol, isopropanol,
toluene, butanol, isobutanol, t-butanol, tetrahydrofuran,
methyltetrahydrofuran, cyclohexane and a mixture thereof, the
solvent is more preferably selected from the group consisting of
ethyl acetate, methanol, CH.sub.2Cl.sub.2 and a mixture
thereof.
Regarding the temperature of the crystallization process there is
no specific limitation provided that the crystalline form (I-Cl) is
obtained. Preferably the temperature is in the range of from -30 to
70.degree. C., more preferably in the range of from 10 to
50.degree. C., even more preferably in the range of from 10 to
30.degree. C.
Use as Antagonists of Orexin Receptor Activity
The compound of formula (IX) obtained or obtainable by the
above-described process or a pharmaceutical composition comprising
this compound is useful in a method of antagonizing orexin receptor
activity. Thus, the present invention also describes the compound
of formula (IX) obtained or obtainable by the above-described
process or a pharmaceutical composition comprising this compound
for use as antagonists of orexin receptor activity, in particular
for use in treating, preventing, ameliorating, controlling or
reducing the risk of a variety of neurological and psychiatric
disorders associated with orexin receptors, in particular for
enhancing the quality of sleep; augmenting sleep maintenance;
increasing REM sleep; increasing stage 2 sleep; decreasing
fragmentation of sleep patterns; treating insomnia; enhancing
cognition; increasing memory retention; treating or controlling
obesity; treating or controlling depression; treating, controlling,
ameliorating or reducing the risk of epilepsy, including absence
epilepsy; treating or controlling pain, including neuropathic pain;
treating or controlling Parkinson's disease; treating or
controlling psychosis; or treating, controlling, ameliorating or
reducing the risk of schizophrenia, in a mammalian patient in need
thereof.
In particular, the compound of formula (IX) obtained or obtainable
by the above described process or a pharmaceutical composition
comprising this compound is used for treating or preventing a sleep
disorder, in particular for enhancing the quality of sleep or for
treating insomnia in a mammalian patient, in particular, for
treating or controlling obesity in a mammalian patient.
As used herein, the terms "treatment" and "treating" refer to all
processes wherein there may be a slowing, interrupting, arresting,
controlling, or stopping of the progression of the neurological and
psychiatric disorders described herein, but does not necessarily
indicate a total elimination of all disorder symptoms, as well as
the prophylactic therapy of the mentioned conditions, particularly
in a patient who is predisposed to such a disease or disorder.
By way of example, the following particularly preferred embodiments
of the invention are mentioned: 1. A process for the preparation of
a compound of formula (A)
##STR00261## or a pharmaceutically acceptable salt or solvate
thereof, wherein (A) is preferably
##STR00262## wherein R.sup.1 is selected from the group consisting
of H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00263## and wherein R.sup.2 is selected from the group
consisting of H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00264## and wherein PG.sup.1 and PG.sup.2 are, independently
of each other, suitable protecting groups, and wherein n is 0 or 1,
the process comprising (a) providing a compound of formula (II)
##STR00265## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, (b) reacting the compound of
formula (II) with a base and optionally reducing the compound to
give the compound of formula (A), (c) optionally crystallizing the
compound of formula (A). 2. The process according to embodiment 1,
wherein the compound of formula (A) has the structure of formula
(Ia)
##STR00266## 3. The process according to embodiment 1 or 2, wherein
the compound of formula (A) has the structure of formula (Ia*)
##STR00267## 4. The process according to embodiment 1, wherein the
compound of formula (A) has the structure of formula (Ib)
##STR00268## and wherein in step (b) upon reaction with the base a
compound of formula (Ia) is formed,
##STR00269## and wherein step (b) further comprises reducing the
compound of formula (Ia). 5. The process according to embodiment 4,
wherein the compound of formula (A) has the structure of formula
(Ib*)
##STR00270## and wherein in step (b) upon reaction with the base a
compound of formula (Ia*) is formed,
##STR00271## and wherein step (b) further comprises reducing the
compound of formula (Ia*). 6. The process according to any of
embodiments 1 to 5, wherein PG.sup.1 is selected from the group
consisting of Benzyl (Bn), t-butyloxycarbonyl (Boc), Cbz
(carboxybenzyl), PNZ (p-Nitrobenzylcarbamoyl)), allyloxycarbonyl
(Alloc), Trifluoroacetate and Phthalimide. 7. The process according
to any of embodiments 1 to 6, wherein PG.sup.2 is selected from the
group consisting of Benzyl, t-butyloxycarbonyl (Boc), Cbz
(carboxybenzyl), PNZ, allyloxycarbonyl (Alloc), Trifluoroacetate
and Phthalimide. 8. The process according to any of embodiments 1
to 7, wherein R1 is selected from the group consisting of H,
##STR00272## more preferably, wherein R1 is H. 9. The process
according to any of embodiments 1 to 8, wherein step (b) comprises
(b1) reacting the compound of formula (II) with a base to give a
composition comprising a compound of formula (Ia)
##STR00273## preferably a compound of formula (Ia*)
##STR00274## (b2) optionally purifying the composition obtained in
(b1), (b3) optionally reducing the compound of formula (Ia),
preferably of formula (Ia*), to give a compound of formula (Ib)
##STR00275## preferably (Ib*)
##STR00276## (b4) optionally purifying the compound obtained in
(b3), wherein preferably the purifying comprises crystallizing the
compound obtained in (b3). 10. The process according to embodiment
9, wherein (b1) is carried out in an organic solvent, more
preferably in a solvent selected from the group consisting of
methanol, ethanol, propanol, isopropanol, butanol, s-butanol,
t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran,
methyltertbutylether, diethylether, diisopropylether, toluene,
acetonitrile and mixtures of two or more thereof 11. The process
according to embodiment 9 or 10, wherein step (b1) is carried out
at a temperature in the range of from -20.degree. C. to 80.degree.
C., more preferably in the range of from 0 to 50, more preferably
in the range of from 20 to 30.degree. C. During the reaction, the
temperature may be varied or held essentially constant. 12. The
process according to any of embodiments 9 to 11, wherein (b3) is
carried out in an organic solvent, more preferably in a solvent
selected from the group consisting of methanol, ethanol, nPrOH,
i-PrOH, THF, 2-MeTHF, MTBE, DIPET, toluene, acetonitrile,
CH.sub.2Cl.sub.2 and mixtures of two or more thereof. 13. The
process according to any of embodiments 9 to 12, wherein in step
(b3), the compound is reduced by reaction with a reducing agent
selected from the group consisting of NaBH.sub.4, NaCNBH.sub.3,
NaBH(OAc)).sub.3, LiAlH.sub.4, LiBH.sub.4 and H.sub.2 in the
presence of at least one transition metal. 14. The process
according to any of embodiments 1 to 13, wherein compound (II)
consists of a mixture of
##STR00277## 15. The process of embodiment 14, wherein compound
(II) contains of from 20 to 75% by weight % of the compound of
formula (II*) based on the total weight of the sum of (II*) and
(II**) and wherein mixture is resolved by chiral resolution to give
the compound (II*). 16. The process of embodiment 15, wherein the
resolution is carried out by a process comprising (i) adding a
single stereoisomer of a chiral acid and precipitating, preferably
crystallizing, a chiral acid salt (S) of compound (II), thereby
obtaining a mixture comprising the precipitated, preferably
crystallized, tartaric acid salt (S) and the solvent, (ii)
preferably separating the precipitated, preferably crystallized,
chiral acid salt (S) of the compound of formula (II) from the
mixture obtained in (i), wherein the chiral acid salt (S) contains
at least 80% by weight of the chiral acid salt of the compound of
formula (II*) based on the total weight of the chiral acid salt of
the compound of formula (II), (iii) converting the chiral acid salt
(S) to the free base. 17. A process of any of embodiments 1 to 17,
wherein the compound has the structure
##STR00278## or is a pharmaceutically acceptable salt or solvate
thereof, wherein (Ia) is preferably (Ia*)
##STR00279## and wherein R.sup.1 is H and R.sup.2 is PG.sup.2. 18.
The process according to any of embodiments 1 to 13, wherein step
(a) comprises (a1) reacting a compound of formula (III)
##STR00280## with a compound of formula (IV)
##STR00281## to give a compound of formula (V)
##STR00282## wherein R.sup.1a is H, R.sup.1, PG.sup.1, R.sup.A, or
PG.sup.1a and wherein R.sup.2a is H, R.sup.2, PG.sup.2, R.sup.B or
PG.sup.2a and wherein PG.sup.1a and PG.sup.2a are, independently of
each other, suitable protecting groups, (a2) optionally purifying
the compound of formula (V), (a3) reducing the compound of formula
(V), (a4) optionally replacing R.sup.2a and/or R.sup.1a with
R.sup.1 and/or R.sup.2, to give the compound of formula (II). 19.
The process of embodiment 18, wherein in step (a3), a compound
having the structure
##STR00283## is obtained. 20. The process of embodiment 19, wherein
compound (IIa) contains of from 20 to 75% by weight % of the
compound of formula (IIa*) based on the total weight of the sum of
(IIa*) and (IIa**)
##STR00284## and wherein the mixture is resolved by chiral
resolution to give the compound (IIa*). 21. The process of
embodiment 20, wherein the resolution is carried out by a process
comprising (ia) adding a single stereoisomer of a chiral acid and
precipitating, preferably crystallizing, a chiral acid salt (Sa) of
compound (IIa), thereby obtaining a mixture comprising the
precipitated, preferably crystallized, tartaric acid salt (Sa) and
the solvent, (iia) preferably separating the precipitated,
preferably crystallized, chiral acid salt (Sa) of the compound of
formula (IIa) from the mixture obtained in (ia), wherein the chiral
acid salt (S) contains at least 80% by weight of the chiral acid
salt of the compound of formula (IIa*) based on the total weight of
the chiral acid salt of the compound of formula (IIa), (iiia)
converting the chiral acid salt (Sa) to the free base. 22. The
process of any of embodiments 1 to 21, wherein step (a) comprises
(a1) reacting a compound of formula (III)
##STR00285## with a compound of formula (IV)
##STR00286## to give a compound of formula (V)
##STR00287## wherein R.sup.1a is PG.sup.1 and wherein R.sup.2a is
H, and PG.sup.1a is a suitable protecting group, preferably a Boc
group, (a2) optionally purifying the compound of formula (V), (a3)
reducing the compound of formula (V) to give a compound of formula
(IIa), wherein R.sup.1a is PG.sup.1 and wherein R.sup.2a is H (a4)
replacing R.sup.2a with
##STR00288## by reacting a compound of formula (IIa) with a
compound of formula (XI)
##STR00289## wherein E is --COOH or a reactive carboxy group, and
replacing R.sup.1a with H by removing the protecting group
PG.sup.1. to give the compound of formula (II) in which R.sup.1 is
H and R.sup.2 is
##STR00290## 23. The process according to any of embodiments 18 to
22, wherein step (a1) is carried out at a temperature in the range
of 0 to 80 C, more preferably in the range of from 10 to 50.degree.
C., more preferably in the range of from 20 to 35.degree. C. 24.
The process according to any of embodiments 18 to 23, wherein (a1)
is carried out in an organic solvent, more preferably in a solvent
methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF,
DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol,
s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran,
methyltertbutylether, diethylether, diisopropylether, toluene,
acetonitrile and mixtures of two or more thereof. 25. The process
according to any of embodiments 18 to 24, wherein (a1) is carried
in the presence of a catalysing agent, such as a dehydrating
reagent or an acidic catalyst, preferably in the presence of
SiO.sub.2 or a molecular sieve or a mixture thereof. 26. The
process according to any of embodiments 28 to 25, wherein (a3) is
carried out in an organic solvent, more preferably in a solvent
selected from the group consisting of methanol, ethanol,
trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol,
ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol,
tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether,
diethylether, diisopropylether, toluene, acetonitrile and mixtures
of two or more thereof. Preferably, the solvent is methanol or TFE.
27. The process according to any of embodiments 18 to 26, wherein
(a3) is carried out at a temperature in the range of from 10 to
100.degree. C., more preferably in the range of from 20 to
60.degree. C., more preferably at 25 to 40.degree. C. 28. The
process according to any of embodiments 18 to 27, wherein in step
(a3), the compound is reduced with Pd/C. 29. The process according
to any of embodiments 18 to 28, wherein in step (a3), the compound
is stereoselectively reduced to give a compound of formula
(IIa*)
##STR00291## 30. The process according to embodiment 29, wherein
the metal catalyst is selected from the group consisting of a
catalyst comprising Pd, Fe, Ir, Rh or a mixture of two or more
thereof. 31. The process according to any of embodiments 1 to 25,
wherein the base in step (b) is selected from the group consisting
of NaOR.sup.E, Na-tert.butoxid, K-tert.butoxid, NaNH2, DBU,
Tetramethylguanidin, Na--CH.sub.2S(O)CH.sub.3 and mixtures of two
or more thereof, with R.sup.E being selected from the group
consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E methyl, ethyl or propyl, more preferably
wherein R.sup.E is methyl, most preferably wherein the base is
sodium methanolate. 32. The process of any of embodiments 1 to 31,
wherein compound (A) has the structure (Ia)
##STR00292## or is a pharmaceutically acceptable salt or solvate
thereof, wherein (Ia) is preferably (Ia*)
##STR00293## and wherein R.sup.1 is H and R.sup.2 is PG.sup.2, the
process comprising (a) providing a compound of formula (II)
##STR00294## preferably of formula (II*), wherein R.sup.E is
selected from the group consisting of H, alkyl, aryl, alkylaryl,
heteroaryl, cycloalkyl and heterocycloalkyl, more preferably
wherein R.sup.E is alkyl, more preferably wherein R.sup.E is
methyl, ethyl or propyl, more preferably wherein R.sup.E is methyl,
(b) reacting the compound of formula (II), preferably of formula
(II*), with a base, to give the compound of formula (Ia), with
R.sup.1 being H and with R.sup.2 being PG.sup.2, preferably (Ia*)
with R.sup.1 being H and with R.sup.2 being PG.sup.2. 33. The
process of any of embodiments 1 to 31, wherein compound (A) has the
structure (Ib)
##STR00295## or is a pharmaceutically acceptable salt or solvate
thereof, wherein (Ib) is preferably (Ib*),
##STR00296## and wherein R.sup.1 is H and R.sup.2 is PG.sup.2, the
process comprising (a) providing a compound of formula (II),
##STR00297## preferably (II*), wherein R.sup.E is selected from the
group consisting of H, alkyl, aryl, alkylaryl, heteroaryl,
cycloalkyl and heterocycloalkyl, more preferably wherein R.sup.E is
alkyl, more preferably wherein R.sup.E is methyl, ethyl or propyl,
more preferably wherein R.sup.E is methyl, (b) reacting the
compound of formula (II) with a base, and reducing the resulting
compound of formula (Ia), to give the compound of formula (Ib),
with R.sup.1 being H and with R.sup.2 being PG.sup.2 preferably
(Ib*) with R.sup.1 being H and with R.sup.2 being PG.sup.2 (c)
optionally preparing a salt of the compound of formula (Ib),
wherein preferably the slat is an hydrochloride salt or a sulphate
salt, (d) optionally crystallizing the compound obtained in (b) or
obtained in (c). 34. The process of any of embodiments 1 to 33,
wherein compound (A) has the structure (VIIa) with R.sup.1 being
H
##STR00298## preferably (VIIa*)
##STR00299## the process comprising (a) providing a compound of
formula (II),
##STR00300## preferably (II*)
##STR00301## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, and wherein R.sup.2 is
##STR00302## (b) reacting the compound of formula (II), preferably
(II*), with a base to give the compound of formula (Vila),
preferably (VIIa*). 35. The process of any of embodiments 1 to 33,
wherein compound (A) has the structure (VIIb) with R.sup.1 being
H
##STR00303## preferably (VIIb*)
##STR00304## the process comprising (a) providing a compound of
formula (II),
##STR00305## preferably (II*), wherein R.sup.E is selected from the
group consisting of H, alkyl, aryl, alkylaryl, heteroaryl,
cycloalkyl and heterocycloalkyl, more preferably wherein R.sup.E is
alkyl, more preferably wherein R.sup.E is methyl, ethyl or propyl,
more preferably wherein R.sup.E is methyl, and wherein R.sup.2
is
##STR00306## (b) reacting the compound of formula (II), preferably
(II*), with a base, and reducing the resulting compound to give a
compound of formula (VIIb), preferably (VIIb*) wherein (b)
comprises (b1-1) optionally preparing a salt of the compound of
formula (VIIb) in which R.sup.1 is H, preferably (VIIb*) in which
R.sup.1 is H and preferably wherein the salt is an hydrochloride
salt or a sulphate salt, (b1-2) optionally purifying the compound
obtained in (b) or (b1-1), wherein preferably purifying comprises
crystallizing the compound obtained in (b) or (b1-1), (b1-3)
optionally transforming the crystalline salt of (b1-2) in the free
base of formula (VIIb), preferably (VIIb*). 36. The process of any
of embodiments 1 to 33, wherein compound (A) has the structure
##STR00307## or is a pharmaceutically acceptable salt or solvate
thereof, wherein (Ia) is preferably (Ia*)
##STR00308## and wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00309## and R.sup.2 is PG.sup.2, the process comprising (a)
providing a compound of formula (II)
##STR00310## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, wherein R.sup.1 is R.sup.A
with R.sup.A being
##STR00311## and R.sup.2 is PG.sup.2, preferably the compound of
formula (Ia*), wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00312## and R.sup.2 is PG.sup.2, (b) reacting the compound of
formula (II) with a base, to give the compound of formula (Ia),
wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00313## and R.sup.2 is PG.sup.2, preferably the compound of
formula (Ia*), wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00314## and R.sup.2 is PG.sup.2, or compound (A) has the
structure
##STR00315## or is a pharmaceutically acceptable salt or solvate
thereof, wherein (Ia) is preferably (Ia*)
##STR00316## and wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00317## and R.sup.2 is PG.sup.2, the process comprising (a)
providing a compound of formula (II)
##STR00318## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, wherein R.sup.1 is R.sup.A
with R.sup.A being
##STR00319## and R.sup.2 is PG.sup.2, preferably the compound of
formula (Ia*), wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00320## and R.sup.2 is PG.sup.2, (b) reacting the compound of
formula (II) with a base, and reducing the resulting compound to
give the compound of formula (Ib), wherein R.sup.1 is R.sup.A with
R.sup.A being
##STR00321## and R.sup.2 is PG.sup.2, preferably the compound of
formula (Ia*), wherein R.sup.1 is R.sup.A with R.sup.A being
##STR00322## and R.sup.2 is PG.sup.2. 37. The process according to
any of embodiments 1 to 33, wherein the compound of formula (A) has
the structure of formula (IX)
##STR00323## 38. The process according to any of embodiments 1 to
37, wherein R.sup.2 in the compound of formula (A) is H, and
wherein in (b) a compound of formula (A1) consisting of an
enantiomeric mixture of the compounds (A1*) and (A1**) is
obtained
##STR00324## wherein the compound of formula (A1) contains of from
20 to 75% by weight, of the compound of formula (A1*) based on the
total weight of the sum of (A1*) and (A1**), step (b) further
comprising (I) forming a chiral acid salt, preferably a tartaric
acid salt, (T*) of at least part of the compound of formula (A1) by
treating the compound of formula (A1) with a single stereoisomer of
a chiral acid salt, preferably of a tartaric acid derivative
selected from the group consisting of Ditoluoyl tartaric acid,
Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl
tartaric acid mono(dimethylamide) and a mixture of two or more
thereof, in a suitable solvent, and precipitating, preferably
crystallizing, at least part of the tartaric acid salt (T*) formed,
thereby obtaining a mixture comprising the precipitated, preferably
crystallized, tartaric acid salt (T) and the solvent; (II)
preferably separating the precipitated, preferably crystallized,
chiral acid salt (T) of the compound of formula (A1) from the
mixture obtained in (I), wherein the chiral acid salt (T) of the
compound of formula (A1) contains at least 80% by weight of the
chiral acid salt of the compound of formula (A1*) based on the
total weight of the chiral acid salt of the compound of formula
(A1), (III) converting the chiral acid salt (T) of (A1) to the free
base (A1*), wherein (A) is preferably (A1*) or wherein (A1*) is
converted in further steps to give (A). 39. The process according
to embodiment 38, wherein the chiral acid salt (T) of the compound
formula (A1) contains at least 90% by weight, more preferably at
least 95% by weight, more preferably at least 96% by weight, more
preferably at least 97% by weight, more preferably at least 98% by
weight, more preferably at least 99% by weight, more preferably at
least 99.5% by weight, more preferably at least 99.9% by weight, of
the tartaric salt of the compound of formula (A1*), based on the
total weight of chiral acid salt of the compound of formula (A1).
40. The process according to embodiment 38 or 39, wherein the
compound of formula (A1) employed in step (I) contains of from 40
to 60% by weight of the compound of formula (A1*) based on the
total weight of the sum of (A1*) and (A1**). 41. The process of any
of embodiments 38 to 40, wherein n is 1 and the chiral acid is
di-toluoyl-L-tartaric acid (LTTA), or n is 0, and the chiral acid
is di-benzoyl-D-tartaric acid (DBTA). 42. The process of embodiment
35 to 39, wherein the suitable solvent in step (I) is selected from
the group consisting of selected from the group consisting of
consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE,
CH.sub.2Cl.sub.2, ethyl acetate, acetone, isopropanol, methanol,
water, formic acid ethyl ester, isopropyl acetate, propyl acetate,
butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane,
methylisobutylketone, toluene, hexane, cyclohexane, heptane and
mixtures of two or more thereof. 43. Process for the preparation of
a compound of formula (IX), comprising (A) preparing a compound of
formula (A) according to the method of any of embodiments 1 to 42,
wherein in case n=0, at least one of R.sup.A or R.sup.B is H or a
protecting group, (B) transforming the compound of step (A) into
the compound of formula (IX). 44. The process of embodiment 43,
wherein (A) comprises providing a compound of formula (Ia) by a
process comprising (a) providing a compound of formula (II)
##STR00325## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, wherein R.sup.1 is H and
R.sup.2 is PG.sup.2, (b) reacting the compound of formula (II) with
a base, to give the compound of formula (Ia), with R.sup.1 being H
and with R.sup.2 being PG.sup.2, preferably (Ia*) with R.sup.1
being H and with R.sup.2 being PG.sup.2. 45. The process of
embodiment 44, wherein step (B) comprises (c1) removal of the
protecting group PG.sup.2, (d1) reacting the compound of formula
(Ia) with R.sup.1 and R.sup.2 being H with a compound of
formula
##STR00326## wherein E is --COOH or a reactive carboxy group, to
give a compound of formula (Vila), in which R.sup.1 is H,
##STR00327## preferably
##STR00328## (e1) reducing the compound, to give a compound of
formula (VIIb), in which R.sup.1 is H
##STR00329## preferably
##STR00330## (f1) reacting the compound of formula (VIIb),
preferably (VIIb*), with a compound of formula (XII)
##STR00331## wherein X* is a leaving group, preferably Cl, S, SMe,
SEt, Br, more preferably --Br or --Cl, more preferably --Cl wherein
(e1) optionally comprises (e1-1) preparing a salt of the compound
of formula (VIIb) in which R.sup.1 is H, preferably (VIIb*) in
which R.sup.1 is H and preferably wherein the salt is an
hydrochloride salt or a sulphate salt, (e1-2) optionally purifying
the compound obtained in (e1) or (e1-1), wherein preferably
purifying comprises crystallizing the compound obtained in (e1) or
(e1-1), (e1-3) optionally transforming the crystalline salt of
(e1-2) in the free base of formula (VIIb), preferably (VIIb*). 46.
The process of embodiment 43, comprising (A) providing a compound
of formula (Ib) by a process comprising (a) providing a compound of
formula (II), preferably (II*),
##STR00332## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, wherein R.sup.1 is H and
R.sup.2 is PG.sup.2. (b) reacting the compound of formula (II) with
a base, to give the compound of formula (Ia)
##STR00333## with R.sup.1 being H and with R.sup.2 being PG.sup.2,
preferably (Ia*) with R.sup.1 being H and with R.sup.2 being
PG.sup.2, and reducing the resulting compound of formula (Ia),
preferably (Ia*), (B) transforming the compound of step (A) into
the compound of formula (IX). 47. The process of embodiment 46,
wherein step (B) comprises (c1) removal of the protecting group
PG.sup.2, (d1b) reacting the compound of formula (Ib) with R.sup.1
and R.sup.2 being H with a compound of formula
##STR00334## wherein E is --COOH or a reactive carboxy group, to
give a compound of formula (VIIb), in which R.sup.1 is H,
##STR00335## preferably
##STR00336## (f1) reacting the with a compound of formula (VIIb),
preferably (VIIb*), with a compound of formula (XII)
##STR00337## wherein X* is a leaving group, preferably Cl and
wherein wherein (d1b) optionally comprises (d1b-1) preparing a salt
of the compound of formula (VIIb) in which R.sup.1 is H, preferably
(VIIb*) in which R.sup.1 is H and preferably wherein the salt is an
hydrochloride salt or a sulphate salt, (d1b-2) optionally purifying
the compound obtained in (d1b) or (d1b-1), wherein preferably
purifying comprises crystallizing the compound obtained in (d1b) or
(d1b-1), (d1b-3) optionally transforming the crystalline salt of
(d1b-2) in the free base of formula (VIIb), preferably (VIIb*). 48.
The process of embodiment 43 comprising (A) providing a compound of
formula (VIIb) by a process comprising (a) providing a compound of
formula (II), preferably (IP),
##STR00338## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, and wherein R.sup.2 is
##STR00339## (b) reacting the compound of formula (II), preferably
(II*), with a base to give the compound of formula (Vila),
preferably (VIIa*), and reducing the resulting compound to give a
compound of formula (VIIb), preferably (VIIb*), (B) transforming
the compound of step (A) into the compound of formula (IX) wherein
(b) optionally comprises (b1-1) preparing a salt of the compound of
formula (VIIb) in which R.sup.1 is H, preferably (VIIb*) in which
R.sup.1 is H and preferably wherein the salt is an hydrochloride
salt or a sulphate salt, (b1-2) optionally purifying the compound
obtained in (b) or (b1-1), wherein preferably purifying comprises
crystallizing the compound obtained in (b) or (b1-1), (b1-3)
optionally transforming the crystalline salt of (b1-2) in the free
base of formula (VIIb), preferably (VIIb*). 49. The process of
embodiment 48, wherein step (B) comprises (f1) reacting the
compound of formula (VIIb), preferably (VIIb*), with a compound of
formula (XII)
##STR00340## wherein X* is a leaving group, preferably Cl. 50. The
process of embodiment 43 comprising (A) providing a compound of
formula (VIIa) by a process comprising (a) providing a compound of
formula (II)
##STR00341## wherein R.sup.E is selected from the group consisting
of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and
heterocycloalkyl, more preferably wherein R.sup.E is alkyl, more
preferably wherein R.sup.E is methyl, ethyl or propyl, more
preferably wherein R.sup.E is methyl, and wherein R.sup.2 is
##STR00342## (b) reacting the compound of formula (II) with a base,
to give the compound (VIIa), preferably (VIIa*), with
R.sup.1.dbd.H, (B) transforming the compound of step (A) into the
compound of formula (IX). 51. The process of embodiment 50, wherein
step (B) further comprises (e1) reducing the compound, to give a
compound of formula (VIIb), in which R.sup.1 is H, preferably
(VIIb*) in which R.sup.1 is H, (f1) reacting the compound of
formula (VIIb), preferably (VIIb*), with a compound of formula
(XII)
##STR00343## wherein X* is a leaving group, preferably Cl and
wherein (e1) optionally comprises (e1-1) preparing a salt of the
compound of formula (VIIb), preferably (VIIb*) wherein preferably
the salt is an hydrochloride salt or a sulphate salt, (e1-2)
optionally purifying the compound obtained in (e1) or (e1-1),
wherein preferably purifying comprises crystallizing the compound
obtained in (e1) or (e1-1), (e1-3) optionally transforming the
crystalline salt of (e1-2) in the free base of formula (VIIb),
preferably (VIIb*). 52. A compound of formula (A) or a salt
thereof, obtained or obtainable by a method of any of embodiments 1
to 42. 53. The compound of embodiment 52, wherein R.sup.1 is H and
R.sup.2 is
##STR00344## 54. The compound of embodiment 53 or the salt thereof
in crystalline form, wherein the compound preferably has the
structure
##STR00345## more preferably the structure
##STR00346## and wherein compound of formula (VIIb) wherein R.sup.1
is H1) has an X-ray powder diffraction pattern comprising a peak at
2-theta angle of approximately 12.4.degree..+-.0.2.degree.,
preferably has an X-ray powder diffraction pattern comprising peaks
at 2-theta angles of approximately 4.8.+-.0.2.degree.,
12.4.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree.,
19.9.degree..+-.0.2.degree. and 20.8.degree..+-.0.2.degree. or at
approximately 7.7.+-.0.2.degree., 11.4.degree..+-.0.2.degree.,
12.4.degree..+-.0.2.degree., 16.2.degree..+-.0.2.degree. and
18.1.degree..+-.0.2.degree., more preferably, at approximately
4.8.+-.0.2.degree., 12.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 19.9.degree..+-.0.2.degree. and
20.8.degree..+-.0.2.degree., wherein the X-ray powder diffraction
pattern is measured at a temperature in the range of from 15 to
25.degree. C. with Cu-K.alpha..sub.1,2 radiation having a
wavelength of 0.15419 nm or 2) has an X-ray powder diffraction
pattern comprising a peak at 2-theta angle of approximately
12.4.degree..+-.0.2.degree., more preferably has an X-ray powder
diffraction pattern comprising peaks at 2-theta angles of
approximately 4.8.+-.0.2.degree., 12.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 19.9.degree..+-.0.2.degree. and
20.8.degree..+-.0.2 and wherein preferably the X-ray powder
diffraction pattern further comprises peaks at one or more than one
or all of 2-theta angles of 21.6.degree..+-.0.2.degree.,
22.6.degree..+-.0.2.degree. 22.9.degree..+-.0.2 and
27.8.degree..+-.0.2.degree. wherein the X-ray powder diffraction
pattern is measured at a temperature in the range of from 15 to
25.degree. C. with Cu-K.alpha..sub.1,2 radiation having a
wavelength of 0.15419 nm. 55. A compound of formula (IX)
##STR00347## obtained or obtainable according to any of embodiments
43 to 51. 56. The compound of embodiment 55, wherein the compound
contains less than 5% by weight, more preferably less than 2% by
weight, more preferably less than 1% by weight, more preferably
less than 100 ppm, of the regio-isomeric side product (IX-S) as
impurity
##STR00348## based on the total weight of the compound (IX), which
includes the compound (IX-S). 57. A compound of formula (A)
##STR00349## or a pharmaceutically acceptable salt or solvate
thereof, wherein (A) is preferably
##STR00350## wherein R.sup.1 is selected from the group consisting
of H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00351## and wherein R.sup.2 is selected from the group
consisting of H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00352## and wherein PG.sup.1 and PG.sup.2 are, independently
of each other, suitable protecting groups, and wherein n is 0 or 1,
and wherein in case n=0 and R.sup.1 is R.sup.A, R.sup.2 is not
R.sup.B or H or, wherein in case n=0 and R.sup.1 is R.sup.A R.sup.B
is PG.sup.1 and wherein in case n=0 and R.sup.1 is H, R.sup.2 is
not R.sup.B or, wherein in case n=0 and R.sup.1 is H, R.sup.2 is H
or PG.sup.2 and wherein in case n=0 and R.sup.1 is Cbz R.sup.2 is
not H or Boc or R.sup.B and wherein when n=1 R.sup.1 and R.sup.2
are not both H. 58. A compound of formula (A)
##STR00353## or a pharmaceutically acceptable salt or solvate
thereof, wherein (A) is preferably
##STR00354## wherein n is 1 R.sup.1 is selected from the group
consisting of H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00355## and R.sup.2 is selected from the group consisting of
H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00356## and PG.sup.1 and PG.sup.2 are, independently of each
other, suitable protecting groups, and wherein when n=1 R.sup.1 and
R.sup.2 are not both H. 59. The compound of embodiment 58, wherein
R.sup.1 is H. 60. The compound of embodiment 59, wherein R.sup.2 is
H. 61. The compound of embodiment 58 or 59, wherein R.sup.2 is
R.sup.B 62. The compound according to any of embodiments 57, 58 or
59 having the structure of formula (VI)
##STR00357## wherein PG.sup.2 is a suitable protecting group,
preferably Cbz. 63. The compound of embodiment 58 or 60 wherein
R.sup.1 is R.sup.A, wherein R.sup.A is preferably
##STR00358## 64. The compound according to embodiment 57 or 58,
having the structure of formula (VIII)
##STR00359## wherein R.sup.2H or PG.sup.2 and PG.sup.2 is a
suitable protecting group. 65. The compound of any of embodiment 58
to 62 having the structure of formula (VI)
##STR00360## wherein PG.sup.1 is a suitable protecting group,
preferably Boc. 66. The compound of embodiment 57 or 58 having the
structure
##STR00361## preferably
##STR00362## wherein when n=1 R.sup.1 is H or PG.sup.1 and PG.sup.1
is a suitable protecting group, preferably wherein PG.sup.1 is Boc,
more preferably wherein R.sup.1 is H and wherein when n=0 R.sup.1
is PG.sup.1 and PG.sup.1 is a suitable protecting group, preferably
wherein PG.sup.1 is Boc. 67. A crystalline form of the compound
according to any of embodiments 57 to 66 or a crystalline form of
the salt of the compound according to any of embodiments 57 to 66.
68. A crystalline form of the compound of formula (VIIb) or of
formula (VIIb*)
##STR00363## or of a salt thereof, wherein R.sup.1 is as defined
above, preferably R.sup.1 is H. 69. The crystalline form of
embodiment 67 or 68, wherein the salt is selected from the group
consisting of hydrochloride salt or (hydrogen) sulphate salt. 70.
Crystalline form (A) of the compound of formula
##STR00364## 1) which has an X-ray powder diffraction pattern
comprising a peak at 2-theta angle of approximately
12.4.degree..+-.0.2.degree., preferably has an X-ray powder
diffraction pattern comprising peaks at 2-theta angles of
approximately 4.8.+-.0.2.degree., 12.4.degree..+-.0.2.degree.,
14.2.degree..+-.0.2.degree., 19.9.degree..+-.0.2.degree. and
20.8.degree..+-.0.2.degree. or at approximately 7.7.+-.0.2.degree.,
11.4.degree..+-.0.2.degree., 12.4.degree..+-.0.2.degree.,
16.2.degree..+-.0.2.degree. and 18.1.degree..+-.0.2.degree., more
preferably, at approximately 4.8.+-.0.2.degree.,
12.4.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree.,
19.9.degree..+-.0.2.degree. and 20.8.degree..+-.0.2.degree.,
wherein the X-ray powder diffraction pattern is measured at a
temperature in the range of from 15 to 25.degree. C. with
Cu-K.alpha..sub.1,2 radiation having a wavelength of 0.15419 nm or
2) which has an X-ray powder diffraction pattern comprising a peak
at 2-theta angle of approximately 12.4.degree..+-.0.2.degree., more
preferably has an X-ray powder diffraction pattern comprising peaks
at 2-theta angles of approximately 4.8.+-.0.2.degree.,
12.4.degree..+-.0.2.degree., 14.2.degree..+-.0.2.degree.,
19.9.degree..+-.0.2.degree. and 20.8.degree..+-.0.2 and wherein
preferably the X-ray powder diffraction pattern further comprises
peaks at one or more than one or all of 2-theta angles of
21.6.degree..+-.0.2.degree., 22.6.degree..+-.0.2.degree.
22.9.degree..+-.0.2 and 27.8.degree..+-.0.2.degree. wherein the
X-ray powder diffraction pattern is measured at a temperature in
the range of from 15 to 25.degree. C. with Cu-K.alpha..sub.1,2
radiation having a wavelength of 0.15419 nm. 71. The crystalline
form of embodiment 70 2), having an X-ray powder diffraction
pattern as disclosed in FIG. 3. 72. Crystalline form (I) of the
compound of formula (VIIb*-H)
##STR00365## having an X-ray powder diffraction pattern comprising
a peak at 2-theta angle of approximately
11.3.degree..+-.0.2.degree., more preferably has an X-ray powder
diffraction pattern comprising peaks at 2-theta angles of
11.3.+-.0.2.degree., 12.3.degree..+-.0.2.degree.,
13.3.degree..+-.0.2.degree., 16.0.degree..+-.0.2.degree.,
20.00.+-.0.2.degree., wherein the X-ray powder diffraction pattern
is measured at a temperature in the range of from 15 to 25.degree.
C. with Cu-K.alpha..sub.1,2 radiation having a wavelength of
0.15419 nm. 73. The crystalline form (I) of embodiment 72, wherein
an X-ray powder diffraction pattern further comprises peaks at
2-theta angles of 16.5.+-.0.2.degree., 18.3.degree..+-.0.2.degree.,
20.1.degree..+-.0.2.degree., 22.7.degree..+-.0.2.degree.. 74. The
crystalline form (I) of embodiment 72 or 73, having an X-ray powder
diffraction pattern as disclosed in FIG. 4. 75. Sulphate salt of
the compound of formula (VIIb) or formula (VIIb*). 76. Crystalline
form (I-S) of the sulphate salt of formula (VIIb*-S)
##STR00366## having an X-ray powder diffraction pattern comprising
a peak at 2-theta angle of approximately
14.3.degree..+-.0.2.degree., more preferably has an X-ray powder
diffraction pattern comprising peaks at 2-theta angles of
7.8.+-.0.2.degree., 8.6.degree..+-.0.2.degree.,
9.1.degree..+-.0.2.degree., 14.3.degree..+-.0.2,
17.4.degree..+-.0.2.degree., 19.7.degree..+-.0.2.degree., wherein
the X-ray powder diffraction pattern is measured at a temperature
in the range of from 15 to 25.degree. C. with Cu-K.alpha..sub.1,2
radiation having a wavelength of 0.15419 nm. 77. The crystalline
form (I-S) of embodiment 76, wherein the X-ray powder diffraction
pattern further comprises peaks at 2-theta angles of
14.7.+-.0.2.degree., 21.7.degree..+-.0.2.degree.,
24.0.degree..+-.0.2.degree.. 78. The crystalline form (I-S) of
embodiment 76 or 77, having an X-ray powder diffraction pattern as
disclosed in FIG. 5. 79. Hydrochloride salt of the compound of
formula (VIIb) or formula (VIIb*). 80. Crystalline form (I-Cl) of
the hydrochloride salt of formula (VIIb*-Cl)
##STR00367## having an X-ray powder diffraction pattern comprising
a peak at 2-theta angle of approximately
15.2.degree..+-.0.2.degree., more preferably has an X-ray powder
diffraction pattern comprising peaks at 2-theta angles of
10.5.+-.0.2.degree., 11.5.degree..+-.0.2.degree.,
15.2.degree..+-.0.2.degree., 16.6.degree..+-.0.2,
22.4.degree..+-.0.2.degree., wherein the X-ray powder diffraction
pattern is measured at a temperature in the range of from 15 to
25.degree. C. with Cu-K.alpha..sub.1,2 radiation having a
wavelength of 0.15419 nm. 81. The crystalline form (I-Cl) of
embodiment 80, wherein an X-ray powder diffraction pattern further
comprises peaks at 2-theta angles of 18.5..+-.0.2.degree.,
23.9.degree..+-.0.2.degree.. 82. The crystalline form (I-Cl) of
embodiment 80 or 81, having an X-ray powder diffraction pattern as
disclosed in FIG. 6. 83. A process for preparing crystalline form
(A) according to embodiment 70 or 71, or for preparing crystalline
form (I) according to any of embodiments 72 to 74 comprising
crystallizing the compound of formula (VIIb) or of formula (VIIb*)
from a solvent wherein preferably the solvent is selected form the
group consisting of ethyl acetate, methanol, CH.sub.2Cl.sub.2,
acetonitrile, isopropyl acetate, acetone, ethanol, isopropanol,
toluene, butanol, isobutanol, t-butanol, tetrahydrofuran,
methyltetrahydrofuran, cyclohexane and mixture thereof, wherein
more preferably the solvent is ethyl acetate. 84. A process for
preparing crystalline form (I-S) according to any of embodiments 76
to 78 or for preparing the crystalline form (I-Cl) according to any
of embodiments 80 to 82 comprising crystallizing the sulphate salt
or the hydrochloride salt of compound of formula (VII*) from a
solvent wherein preferably the solvent is selected form the group
consisting of ethyl acetate, methanol, CH.sub.2Cl.sub.2,
acetonitrile, isopropyl acetate, acetone, ethanol, isopropanol,
toluene, butanol, isobutanol, t-butanol, tetrahydrofuran,
methyltetrahydrofuran, cyclohexane and mixture thereof, wherein the
solvent is more preferably selected from the group consisting of
ethyl acetate, methanol, CH.sub.2Cl.sub.2 and mixture thereof 85.
Use of a compound of formula (A)
##STR00368## preferably of formula (A*)
##STR00369## or a pharmaceutically acceptable salt or solvate
thereof, wherein R.sup.1 is selected from the group consisting of
H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00370## and wherein R.sup.2 is selected from the group
consisting of H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00371## and wherein PG.sup.1 and PG.sup.2 are, independently
of each other, suitable protecting groups, and wherein n in case
n=0, at least one of R.sup.A or R.sup.B is H or a protecting group,
for the preparation of a compound having the structure of formula
(IX)
##STR00372## 86. Use of a compound of formula (II)
##STR00373## preferably of formula (II*)
##STR00374## wherein R.sup.1 is selected from the group consisting
of H, PG.sup.1 and R.sup.A with R.sup.A being
##STR00375## and wherein R.sup.2 is selected from the group
consisting of H, PG.sup.2 and R.sup.B with R.sup.B being
##STR00376## and wherein PG.sup.1 and PG.sup.2 are, independently
of each other, suitable protecting groups for the preparation of a
compound having the structure of formula (IX).
##STR00377## 87. Use of the crystalline form (A) according to
embodiments 70 or 71 for the preparation of a compound having the
structure of formula (IX)
##STR00378## 88. Use of the crystalline form (I) according to any
of embodiments 72 to 74 for the preparation of a compound having
the structure of formula (IX)
##STR00379## 89. Use of the crystalline form (I-S) according to any
of embodiments 76 to 78 for the preparation of a compound having
the structure of formula (IX)
##STR00380## 89. Use of the crystalline form (I-Cl) according to
any of embodiments 80 to 82 for the preparation of a compound
having the structure of formula (IX)
##STR00381##
FIGURES
FIGS. 1 and 2 show preferred synthesis schemes according to the
invention.
FIG. 3 shows a representative X-ray powder diffraction (XRPD)
pattern of the crystalline form of compound (VIIb) according to the
present invention, as determined according to Reference Example
1.
FIG. 4 shows a representative X-ray powder diffraction (XRPD)
pattern of the crystalline form (I) of compound (VIIb*) according
to the present invention, as determined according to Reference
Example 1.
FIG. 5 shows a representative X-ray powder diffraction (XRPD)
pattern of the crystalline form (I-S) of the sulphate salt of
compound (VIIb*) according to the present invention, as determined
according to Reference Example 1.
FIG. 6 shows a representative X-ray powder diffraction (XRPD)
pattern of the crystalline form (I-Cl) of the hydrochloride salt of
compound (VIIb*) according to the present invention, as determined
according to Reference Example 1.
FIG. 7 shows the representative X-ray powder diffraction (XRPD)
pattern of FIGS. 3, 4, 5 and 6 for comparison.
EXAMPLES
Reference Example 1: X-Ray Powder Diffraction Patterns
X-ray powder diffraction patterns (XRPD) as disclosed herein were
obtained with a PANalytical X'Pert PRO diffractometer equipped with
a theta/theta coupled goniometer in transmission geometry,
Cu-K.alpha.1,2 radiation (wavelength 0.15419 nm) with a focusing
mirror and a solid state PIXcel detector. The patterns were
recorded at a tube voltage of 45 kV and a tube current of 40 mA,
applying a step-size of 0.013.degree. 2-Theta with 40 s per step
(255 channels) in the angular range of 2.degree. to 40.degree.
2-Theta at ambient conditions (15 to 25.degree. C.). A typical
precision of the 2-theta values is in the range of about
.+-.0.2.degree. 2-Theta. Thus a diffraction peak that appears at
5.0.degree. 2-Theta can appear between 4.8 and 5.2.degree. 2-Theta
on most X-ray diffractometers under standard conditions.
Example 1: Preparation of (Z)-Methyl
3-((2-((tert.-Butoxycarbonyl)amino)ethyl)amino)but-2-enoate
##STR00382##
Boc-ethylenediamine (84.3 g, 500 mmol) was dissolved in
CH.sub.2Cl.sub.2 (110 mL), transferred into a 500 mL Schmizo and
cooled to 10.degree. C. Silica gel (120 g) was added in portions
and the slurry was diluted with CH.sub.2Cl.sub.2 (50 mL). Methyl
acetoacetate (54 mL, 500 mmol) was added, the reaction mixture was
stirred at 20.degree. C. and the reaction progress was monitored by
GC. The reaction was judged complete after one hour. The silica gel
was filtered off and the filter cake was washed with
CH.sub.2Cl.sub.2 (250 mL). The slightly yellow solution was
concentrated under reduced pressure to give the enamine as slightly
yellow oil (127.9 g).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.57 (br s, 1H), 4.84
(br s, 1H), 4.47 (s, 1H), 3.61 (s, 3H), 3.33 (m, 2H), 3.23 (m, 2H),
1.91 (s, 3H), 1.43 (s, 9H). .sup.13C NMR (75 MHz,
CDCl.sub.3):=170.9, 162.0, 155.9, 82.7, 79.6, 50.0, 42.8, 41.3,
28.3, 19.3. All data are in agreement with the data reported in
literature (see J. Org. Chem. 2010, 75, 6023).
Example 2
Preparation of Methyl
3-((2-((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate via
Hydrogenation
##STR00383##
A solution of the enamine (58.7 g, 227 mmol) in MeOH (650 mL) was
hydrogenated in the presence of 73 g Pd/C at 55.degree. C. at a
pressure of 3 bar. The reaction was monitored by GC. After complete
conversion (approximately 7 hours) the suspension was filtered over
a K150 filter and the solid was washed with MeOH. The solution was
concentrated under reduced pressure, taken up in MeOH (300 mL) and
distilled under reduced pressure to give the .beta.-aminoester
(51.6 g, 87%) as oil.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=5.28 (br s, 1H, NH),
3.99 (br s, 1H, NH) 3.66 (s, 3H, OCH.sub.3), 3.13-3.25 (overlapping
m, 3H, CH.sub.2+CH), 2.78 (m, 2H, CH.sub.2), 2.48 (m, 2H,
CH.sub.2), 1.41 (s, 9H, C(CH.sub.3).sub.3), 1.15 (d, J=6.3 Hz, 3H,
CH.sub.3). .sup.13C NMR (75 MHz, CDCl.sub.3): .delta.=172.2, 156.1,
79.2, 51.6, 50.1, 45.9, 40.6, 39.8, 28.3, 19.7.
Example 3
Preparation of Methyl
3-((2-((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate with an
Enantiomeric Excess of ee=93% via Asymmetric Hydrogenation
##STR00384##
46.2 mg (0.085 mmol) ferrocenyl ligand and 29.0 mg (0.077 mmol)
[Rh(nbd)2]BF4 were placed in a 10 mL Schlenk flask that was
previously set under an atmosphere of argon. Then 6 mL degassed
2,2,2-trifluoroethanol (TFE) was added and the resulting red
solution stirred for 30 min. at 50.degree. C. In a second Schlenk
flask, 0.5 g (1.94 mmol) of enamine ((Z)-methyl
3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)but-2-enoate) was
placed, followed by 14 mL degassed TFE. The clear solution was
stirred for 10 min. Then, both the substrate and the catalyst
solution were transferred via syringe into a 50 mL stainless steel
reactor that was previously set under an atmosphere of argon. The
reactor was sealed, purged with argon in three cycles (1 bar/20
bar) and finally, the argon replaced by hydrogen (4 cycles 1 bar/20
bar). The reactor pressure was set to 10 bar hydrogen, heating to
50.degree. C. and stirring started. After 21 hrs. reaction time,
the autoclave was cooled to ambient temperature and the pressure
released.
The crude product was analyzed by GC with respect to conversion and
chemoselectivity and upon derivatization with
4-chlorobenzoylchloride by chiral HPLC method. The conversion after
21 hrs. was >99.5%, and product 2 (methyl
3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)butanoate) was formed
with approx. 60% chemoselectivity and 93% ee (first-eluting
enantiomer).
Example 4
Preparation of Methyl
3-((2-((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate via
Reduction
##STR00385##
NaBH.sub.4 (33.0 g, 872 mmol) was added in small portions over a
period of 90 minutes into vigorously stirred acetic acid (500 mL)
and the internal temperature was kept between 15-20.degree. C.
Vigorous gas formation was observed as well as the formation of a
thick suspension halfway through the addition. MeCN (250 mL) was
added, the suspension was stirred for 30 minutes and the internal
temperature was adjusted to 0-5.degree. C. A solution of the
enamine (113.0 g, 437 mmol) in MeCN (150 mL) was added over a
period of 45 minutes at 0-5.degree. C. followed by a MeCN-rinse
(100 mL). The reaction mixture was stirred for 2.5 hours at
5.degree. C. before being cautiously quenched with H.sub.2O (100
mL, gas formation). (At that stage the pH was adjusted to pH=7.0
with NaOH (50%) and CH.sub.2Cl.sub.2 (100 mL) was added which
resulted in the formation of two phases. The two phases were
stirred over night: holding point). The pH-value was adjusted to
pH=11.5 with NaOH (50%). In order to avoid the formation of solids
in the aqueous layer H.sub.2O (.about.800 mL) was added. The
organic phase was separated and washed with H.sub.2O. The combined
aqueous phases were extracted twice with ethyl acetate (250 mL
each).
The combined organic phases were dried over Na.sub.2SO.sub.4,
filtered and concentrated to give the filtered and concentrated to
give the
The analytical data were in full agreement with the data obtained
by hydrogenation.
Example 5
Preparation of Methyl
3-((2-((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate with an
Enantiomeric Excess of ee=33% Via Chiral Resolution
Racemic .beta.-aminoester was resolved with tartaric acid to give
enantiomerically enriched .beta.-aminoester.
Example 6
Preparation of 7-Methyl-1,4-diazepan-5-one
##STR00386## Procedure "Cbz-Protection":
H.sub.2O (500 mL) was added to a solution of the .beta.-aminoester
(78.0 g, 300 mmol) in EtOAc (1000 mL) at room temperature. Benyzl
chloroformate (Cbz-Cl, 51.4 mL, 360 mmol) was added slowly and the
pH-value was kept between pH=8-9 by the addition of NaOH (10 M).
The reaction was slightly exotherm and GC indicated complete
conversion of the starting material after 30 minutes. The two
phases were separated and the organic phase was washed with a
saturated NaHCO.sub.3 solution (300 mL). The solution was
concentrated under reduced pressure to give the Cbz-protected amine
quantitatively (128.4 g) as oil. The crude product was used in the
next step without any further purification.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.33-7.39 (m, 6H,
H.sub.arom+NH), 5.13 (s, 2H, OCH.sub.2), 4.32 (br s, 1H, CH), 3.61
(s, 3H, OCH.sub.3), 3.21-3.35 (br m, 4H, CH.sub.2, CH.sub.2),
2.42-2.80 (series of br m, 2H, CH.sub.2), 1.43 (s, 9H,
C(CH.sub.3).sub.3), 1.26 (br s, 3H, CH.sub.3).
Procedure "Boc-Deprotection":
HCl (37 w %, 45 mL, 540 mmol) was added to a stirred solution of
the Boc-protected amine (128.4 g, calcd. as 270 mmol) in MeOH (1200
mL) and the reaction mixture was stirred at 50.degree. C. for two
hours and at 80.degree. C. for one hour. The reaction progress was
monitored by HPLC and the reaction was judged complete after 4
hours. The reaction mixture was concentrated to a volume of
approximately 250 mL. A solid precipitated during the
MeOH-destillation. Acetone (1000 mL) was added dropwise and the
solvent was removed completely. CH.sub.2Cl.sub.2 (300 mL) was added
and then removed by distillation. The product (amine in form of HCl
salt, 116.7 g) was obtained as foam and used in the next step
without any further purification.
Procedure "Cyclization":
NaOMe (51.2 g, 972 mmol) was added to a stirred solution of the
amine. HCl salt (116.2 g, calculated as 243 mmol) im MeOH (1000 mL)
at room temperature. An exotherm reaction was observed. The
reaction mixture was stirred over night at room temperature. The
solids were filtered off over a K150 filter and washed with MeOH
(100 mL). The solution of the crude product was used directly in
the next step without further purification.
A small aliquot was used for characterization. .sup.1H NMR (300
MHz, CDCl.sub.3): .delta.=7.36 (m, 5H, H.sub.arom.), 5.15 (s, 2H,
OCH.sub.2), 4.74 (br m, 2H, NH, CH), 4.25 (br s, 1H, CH.sub.A),
3.34 (m, 1H, CH.sub.X), 3.15 (m, 2H, CH.sub.B, CH.sub.Y), 2.81 (d,
J=14.5 Hz, 1H, CH.sub.P), 2.50 (dd, J=14.5, 5.9 Hz, 1H, CH.sub.Q),
1.26 (d, J=7.0 Hz, 3H, CH.sub.3).
Procedure "Cbz-Deprotection":
The above mentioned solution of the Cbz-protected amine (calcd. as
219 mmol) in MeOH (1100 mL) was concentrated to a volume of
approximately 700 mL. This solution was hydrogenated in the
presence of Pd/C (46 g, 10% Pd) at room temperature at a
H.sub.2-pressure of 2 bar. The hydrogenation was monitored by HPLC
and judged complete after two hours. The suspension was filtered
over a K150 filter and the filter cake was washed with MeOH. The
solution of the crude product was concentrated under reduced
pressure and the residue (71.4 g) was taken up in CH.sub.2Cl.sub.2
(200 mL). The solution was stirred for 30 minutes and the remaining
solids were filtered off. The solution was concentrated and the
residue (30 g) started crystallizing upon standing at room
temperature. MTBE (200 mL) was added and the suspension was stirred
for one hour. The solid was filtered off, washed with MTBE and
dried over night at 40.degree. C./2 mbar to give
7-methyl-1,4-diazepan-5-one (17.4 g, 62%) as colorless
crystals.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.31 (br s, 1H, C(O)NH),
3.28 (m, 1H, CH.sub.A), 2.90-3.14 (series of overlapping m, 3H, CH,
CH.sub.B, CH.sub.X), 2.77 (m, 1H, CH.sub.Y), 2.51 (dd, J=14.1, 9.6
Hz, 1H, CH.sub.P), 2.35 (apparent d, J=14.3 Hz, 1H, CH.sub.Q), 2.03
(br s, 1H, NH), 1.09 (d, J=6.5 Hz, 3H, CH.sub.3). .sup.13C NMR (75
MHz, CDCl.sub.3): .delta.=177.3, 49.4, 47.2, 44.4, 23.6.
Example 7
Chiral Resolution of 7-Methyl-1,4-diazepan-5-one
##STR00387##
Chiral resolutions were achieved with several chiral acids with
varying degree of induction by performing a systematic screening.
Here, the best hit will be described as a representative example.
DTTA corresponds to (-)-Di-O,O'-toluyl-D-tartaric acid and LTTA
corresponds to the enantiomer (+)-Di-O,O'-toluyl-L-tartaric acid. A
solution of the chiral acid (62.8 mg, 0.16 mmol) in MeOH (0.5 mL)
and a solution of racemic 7-methyl-1,4-diazepan-5-one (41.4 mg,
0.32 mmol) in MeOH (0.8 mL) were combined and allowed to
crystallize over night. The solid was filtered and the enantiomeric
excess was determined by HPLC. The enantiomeric ratio was >40:1
in both cases, the absolute stereochemistry is determined according
to literature proceedings.
Example 8
Reaction of Methyl
3-((2-((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate and
5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic Acid
##STR00388##
Oxalyl chloride (14.26 g, 118.1 mmol) was added over a period of 14
minutes to a stirred suspension of
5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic Acid (20.0 g, 98.4 mmol)
in CH.sub.2Cl.sub.2 (132 mL) and DMF (2.0 mL) at 1.degree. C. After
complete addition the reaction mixture was stirred for 30 minutes
at 5.degree. C. An addition funnel was charged with a solution of
3-((2-((tert.-butoxycarbonyl)amino)ethyl)amino)butanoate (24.4 g,
93.7 mmol) in CH.sub.2Cl.sub.2 (340 mL) and NEt.sub.3 (19.0 g,
187.4 mmol). The amine solution was added over a period of 40
minutes to the stirred acid chloride solution at a rate to keep the
internal temperature <10.degree. C. The reaction progress was
monitored by HPLC and the reaction was judged complete after two
hours. The reaction was quenched with H.sub.2O (250 mL) and the
pH-value was adjusted to pH=10.0 by the addition of NaOH (2.0 M).
The organic layer was separated and washed with H.sub.2O (250 mL)
at a pH=2.0 adjusted with HCl (2.0 M). The organic phase was
concentrated under reduced pressure. The residue was taken up in
toluene (100 mL) and concentrated under reduced pressure to give
49.6 g residue. The residue was taken up in cyclohexane (.about.250
mL) and stirred for two hours at room temperature. The solid was
filtered, washed twice with cyclohexane (2.times.20 mL) and dried
(40.degree. C., <5 mbar) to give the product (35.4 g, 84% yield)
as a crystalline solid.
.sup.1H NMR (300 MHz, DMSO-D.sub.6): .delta.=6.77-8.07 (series of
overlapping m, 6H), 3.88-4.37 (series of overlapping m, 1H),
3.42-3.66 (three s, 3H), 2.56-3.35 (series of overlapping m, 6H),
2.39 (three s, 3H), 0.82-1.40 (series of overlapping m, 12H).
Example 9
Preparation of Methyl
3-(N-(2-aminoethyl)-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamido)butanoate
Hydrochloride by Boc-Cleavage
##STR00389##
HCl (1.25 M in MeOH, 136.3 mmol) was added to a solution of the
Boc-protected amine (30.4 g, 68.2 mmol) in MeOH (304 mL) and the
reaction mixture was refluxed. The reaction progress was monitored
by HPLC and judged complete after 5.5 hours. The reaction mixture
was cooled to room temperature and concentrated under reduced
pressure. The residue was taken up in toluene (100 mL) and
concentrated under reduced pressure to give 30.5 g foam.
Crystallization from toluene and cyclohexane gave Methyl
3-(N-(2-aminoethyl)-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamido)bu-
tanoate Hydrochloride (25.1 g, 97%) as a crystalline solid.
.sup.1H NMR (300 MHz, D.sub.2O): .delta.=7.14-7.93 (series of
overlapping m, 5H), 2.88-4.41 (series of overlapping m, 8H),
2.05-2.77 (series of overlapping m, 5H), 1.10-1.33 (series of d,
3H).
Example 10
Preparation of
7-Methyl-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepan-5-one
Via Cyclization of Methyl
3-(N-(2-aminoethyl)-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamido)butanoate
Hydrochloride
##STR00390##
NaOMe (6.0 g, 115.3 mmol) was added to a solution of Methyl
3-(N-(2-aminoethyl)-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamido)butanoate
Hydrochloride (29.34 g, 76.8 mmol) in MeOH (380 mL) at room
temperature and the reaction progress was monitored by HPLC. The
reaction was judged complete after 1.5 hours. The suspension was
diluted with CH.sub.2Cl.sub.2 (380 mL) and H.sub.2O (380 mL) and
the organic layer was separated. The aqueous layer was extracted
twice with CH.sub.2Cl.sub.2 (2.times.200 mL) and the combined
organic phases were concentrated under reduced pressure to give a
residue that was taken up in cyclohexane (100 mL), filtered and
dried to give
7-Methyl-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepan-5-one
(17.6 g, 85% yield) as a crystalline solid. A second
crystallization from the mother liquor gave additional
7-Methyl-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepan-5-one
(1.7 g).
.sup.1H NMR (300 MHz, CDCl.sub.3, suspension): .delta.=7.76-7.90
(m, 3H), 6.94-7.36 (series of m, 3H), 5.35 (m, .about.0.5H), 4.89
(m, .about.0.5H), 3.95-4.09 (series of m, .about.0.5H), 3.21-3.64
(series of overlapping m, 2H), 2.72-3.15 (series of overlapping m,
.about.2.5H), 2.16-2.64 (series of m+s, 4H), 0.92-1.36 (series of
d, 3H).
Example 11
Preparation of
7-Methyl-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepan-5-one
Via Reaction of 7-Methyl-1,4-diazepan-5-one and
5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic Acid
##STR00391##
A solution of oxalyl chloride (1.08 mL, 12.6 mmol) in
CH.sub.2Cl.sub.2 (2 mL) was added over a period of 15 minutes to a
suspension of 5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic Acid (2.13
g, 10.5 mmol) in CH.sub.2Cl.sub.2 (14 mL) and DMF (0.22 mL) at
0-2.degree. C. The resulting clear solution was stirred for 30
minutes at 5.degree. C. An addition funnel was charged with a
solution of 7-Methyl-1,4-diazepan-5-one (1.34 g, 10.0 mmol) in
CH.sub.2Cl.sub.2 (11 mL) and NEt.sub.3 (2.9 mL, 21 mmol) and the
solution was added over a period of 20 minutes. The reaction
mixture was stirred for one hour at 5.degree. C. and the reaction
progress was monitored by HPLC. The reaction was quenched by the
slow addition of H.sub.2O (27 mL) and the two phases were stirred
for 15 minutes. The phases were separated and the organic layer was
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to give 3.3 g of a foam. The crude product was taken up in
MeOH (7.5 mL) and the product was allowed to crystallize over
night. The solid was filtered off, washed with MeOH and dried over
night (40.degree. C., 2 mbar) to give 2.5 g (80% yield)
7-Methyl-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepan-5-one
as a crystalline solid.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.77-7.91 (m, 3H),
6.85-7.37 (series of m, 3H), 5.36 (m, .about.0.5H), 4.90 (m,
.about.0.5H), 3.93-4.13 (series of m, .about.0.5H), 3.21-3.64
(series of overlapping m, 2H, 2.16-3.16 (series of overlapping m,
.about.6.5H), 0.92-1.37 (series of d, 3H). The analytical data are
in full agreement with the data obtained via the other variant
1.
Example 12
Preparation of
(7-Methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)met-
hanone Via Reduction of
7-Methyl-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepan-5-one
##STR00392##
7-Methyl-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepan-5-one
(5.0 g, 15.9 mmol) was added to a suspension of NaBH.sub.4 (6.03 g,
159.9 mmol) in 2-MeTHF (100 mL) and the suspension was warmed to
45.degree. C. TFA (24.6 mL, 318 mmol) was added via syringe pump
over a period of 16 hours at 55.degree. C. (In this case the
reaction did not go to completion. Additional NaBH.sub.4 and TFA
had to be added). The reaction progress was monitored by HPLC and
after complete conversion the reaction mixture was cooled to room
temperature. The reaction was quenched by the addition of brine
(500 mL). The organic phase was separated, washed with H.sub.2O
(200 mL) and dried over MgSO.sub.4. The drying agent was filtered
and the solution was concentrated to give
(7-Methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)met-
hanone (5.59 g) as a white solid.
The crude product was taken up in a mixture (25 mL) of
heptane/ethyl acetate/NEt.sub.3 (1/1.5/0.1) and the solid was
filtered to give
(7-Methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)met-
hanone (3.30 g, 69%) as a crystalline solid.
The XRPD analysis of the crystalline compound of the title gave the
XRPD of FIG. 3
Example 13
Preparation of
R-(7-Methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)m-
ethanone Via Reduction of
7-Methyl-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepan-5-one
##STR00393##
40 g of
R-7-Methyl-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diaz-
epan-5-one (5.0 g, 15.9 mmol) was reduced with the same procedure
of the above example 12. After extraction 63.6 g of crude reduced
compound were obtained. The yield was based on the crude product
was >100%.
The crude product was taken up in EtOAc and the solid was filtered
to give
R-(7-Methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phe-
nyl)methanone as a crystalline solid (2.4 mg) in a yield of 6%
(assayed by HPLC).
The mother liquor was then washed and distilled off to give 33.5 g
of crude reduced compound.
Example 14
Preparation of Hydrochloride Salt of
R-(7-Methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)m-
ethanone
The 33.5 g of
R-(7-Methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)m-
ethanone recovered from the mother liquor were dissolved in
methanolic HCl and the solvent was removed. The formed HCl salt was
crystallized from EtOAc and isolated to give 18.2 g of
hydrochloride salt (42% yield, assay by HPLC: 98.4%).
The XRPD analysis of the crystalline compound of the title gave the
XRPD of FIG. 4.
Example 15
Preparation of Sulfate Salt of
R-(7-Methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)m-
ethanone Crystalline Form (VIIb*-S)
To a stirred solution of
R-(7-Methyl-1-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepan-5--
one) (100 mg, 0.33 mmol, free amine, as is) in 3 mL MeOH and 3 mL
CH.sub.2Cl.sub.2 was added H.sub.2SO.sub.4 (10 .mu.L, 0.18 mmol).
The solvent was removed under reduced pressure to give the compound
of the title as a crystalline residue (73 mg, as is).
The XRPD analysis of the crystalline compound of the title gave the
XRPD of FIG. 5.
Example 16
Preparation of Suvorexant from
(7-Methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)met-
hanone and 2,5-Dichlorobenzoxazol
##STR00394##
Oxalyl chloride (1.20 g, 9.4 mmol) was added dropwise to a stirred
suspension of 2-mercapto-5-chlorobenzoxazol (1.28 g, 6.9 mmol) in
CH.sub.2Cl.sub.2 (37 mL) at <20.degree. C. DMF (4.59 g, 62.8
mmol) was added dropwise. A vigorous gas formation was observed and
the suspension turned into a solution halfway throughout the
addition. The reaction mixture was stirred for 20 minutes. Two
additional aliquots oxalyl chloride (#1:0.20 g, 1.35 mmol; #2:0.40
g, 2.70 mmol) were added and the reaction mixture was stirred for
1.5 hours. HPLC indicated complete conversion of
2-mercapto-5-chlorobenzoxazol into 2,5-Dichlorobenzoxazol.
The solution of 2,5-Dichlorobenzoxazol was added to a solution of
(7-Methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)met-
hanone (1.88 g, 6.3 mmol) and NEt.sub.3 (3.18 g, 6.3 mmol) in DMF
(24 mL) at room temperature. The reaction mixture was then stirred
at 70.degree. C. for 19 hours and at 90.degree. C. for 20 hours.
The reaction mixture was then cooled to room temperature and
quenched with a saturated solution of NaHCO.sub.3 (50 mL). The
organic phase was separated and washed with H.sub.2O (50 mL)
followed by brine (50 mL). The organic phase was dried over
MgSO.sub.4, filtered and concentrated to give crude Suvorexant
(3.58 g).
Example 17
Chiral Resolution of a Diazepane
(a) Formation of (R)-benzyl
5-methyl-1,4-diazepane-1-carboxylate.DBTA (Compound 12)
##STR00395## Small Scale
A solution of DBTA (1.48 g, 4.13 mmol) in acetone (6.5 mL) was
added to a solution of racemic benzyl
5-methyl-1,4-diazepane-1-carboxylate (1.02 g, 4.11 mmol) and
stirred at room temperature. A seeding crystal was added and the
crystallization was stirred for 4 hours at room temperature and for
1 hour at 0.degree. C. The solid was filtered, washed with acetone
(2.5 mL) and dried in vacuo to give 0.44 g (R)-benzyl
5-methyl-1,4-diazepane-1-carboxylate .DBTA (18% yield) with an
enantiomeric ration of e.r.=96.7:3.3.
Large Scale
A solution of DBTA (5.24 g, 14.62 mmol) in acetone (25 mL) was
added to a stirred solution of racemic benzyl
5-methyl-1,4-diazepane-1-carboxylate (7.26 g, 29.24 mmol) in
acetone (30 mL) at 40.degree. C. The onset of the crystallization
occurred after 10 minutes. The crystallization was stirred at
40.degree. C. for 4 hours and at room temperature over night. The
solid was filtered, washed twice with acetone (2.times.8 mL) and
dried under reduced pressure (<50 mbar, 45.degree. C.) to give
5.50 g (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate.DBTA (31%
yield) with an enantiomeric ratio of e.r.=88.3:11.7.
(b) Recrystallization of (R)-benzyl
5-methyl-1,4-diazepane-1-carboxylate.DBTA
##STR00396##
(R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate.DBTA (450 mg, 0.74
mmol) with an enantiomeric ration of e.r.=88.3:11.7 was
re-crystallized from EtOH (5 mL) by forming a solution at
60.degree. C. and crystallizing at room temperature. The solid was
filtered, washed twice with EtOH (2.times.2 mL) and dried to give
(R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate.DBTA (290 mg, 64%
yield) with an enantiomeric ration of e.r.=97.7:2.3.
(c) Isolation of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate
(Compound (enantio)-4) From (R)-benzyl
5-methyl-1,4-diazepane-1-carboxylate.DBTA
##STR00397##
A solution of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate.DBTA
(2.04 g, 3.36 mmol) in CH.sub.2Cl.sub.2 (40 mL) was extracted with
H.sub.2O at pH=12.0 (adjusted with NaOH, 1.0 M). The organic layer
was washed twice with H.sub.2O (2.times.20 mL), concentrated under
reduced pressure and dried in vacuo to give (R)-benzyl
5-methyl-1,4-diazepane-1-carboxylate (1.02 g, quant. yield).
.sup.1H NMR (CDCl.sub.3, 300 MHz, hindered rotation is observed):
d=7.28-7.36 (m, 5H), 5.13 (m, 2H), 3.54-3.78 (m, 2H), 3.32-3.49 (m,
2H), 3.11 (m.about.tt, J=13.1, 3.5 Hz, 1H), 2.70-2.87 (m, 2H), 2.08
(br. s, 1H), 1.89 (m, 1H), 1.47 (m, 1H), 1.13 (d, J=5.9 Hz, 1.5H.
The analytical data are in full agreement with the analytical data
obtained from LKL8-57.
The chirality in (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate
was determined to be R according to the CIP system. The Chirality
was determined by protecting the second amine group with
Boc.sub.2O, by measuring the specific rotation of the product and
comparing it to literature values.
Comparative Example 1
Preparation of Suvorexant According to Org. Process Res. Dev. 2011,
15, 367, WO2012/148553
##STR00398##
##STR00399##
Suvorexant (left) and its regioisomeric impurity (right):
##STR00400## Procedure:
To a solution of the amine. 0.5DBTA salt (4.25 g, 10.0 mmol) in
CH.sub.2Cl.sub.2 (31 mL) was added a solution of NaOH (10 M
solution, 24.6 mL, 246 mmol) in H.sub.2O (40 mL) at room
temperature. The heterogeneous mixture was stirred at room
temperature for one hour. The two phases were separated. A solution
of NaCl (11 g) in H.sub.2O (22 mL) was added to the aqueous phase
followed by the addition of CH.sub.2Cl.sub.2 (5.5 mL). The
heterogeneous mixture was stirred for 10 minutes and the phases
were separated. The organic layers were combined and concentrated
under reduced pressure to a total volume of approximately 11 mL to
give a concentrated solution of the free amine in
CH.sub.2Cl.sub.2.
Oxalyl chloride (1.08 mL, 10.0 mmol) was added dropwise to a
stirred suspension of 5-methyl-2-triazolylbenzoic acid (2.13 g,
10.5 mmol) in CH.sub.2Cl.sub.2 (14 mL) and DMF (0.22 mL) at
0.degree. C.-2.degree. C. and the resulting acid chloride solution
was stirred for 30 minutes.
NEt.sub.3 (2.9 mL, 21 mmol) was added to the solution of the free
amine in CH.sub.2Cl.sub.2 (total volume approximately 11 mL). The
amine solution was then added over a period of 30 minutes to a
stirred solution of the acid chloride (total volume approximately
14 mL) at a rate to keep the internal temperature at 5.degree.
C.-10.degree. C. The reaction mixture was stirred for one hour
before being quenched by the addition of H.sub.2O (27 mL) at a rate
to keep the internal temperature <15.degree. C. The two layers
were separated and the organic phase was concentrated under reduced
pressure to a total volume of approximately 15 mL. Acetonitrile (90
mL) was added followed by the addition of activated charcoal (0.4
g) and the suspension was stirred for 80 minutes at room
temperature. The suspension was filtered, the solid was washed with
acetonitrile and the solution was concentrated under reduced
pressure to a total volume of approximately 18 mL. H.sub.2O was
added to the solution over a period of 40 minutes at 25.degree. C.
The solution was stirred over night. A white precipitate formed
during that period. The solid was filtered, washed twice with
acetonitrile/H.sub.2O (1:5, 5 mL each), washed with H.sub.2O, and
dried over night in vacuo at 45.degree. C. to give Suvorexant (3.1
g, 68%) with an assay of 89.3 area % according to HPLC. The assay
of the "regioisomer" of Suvorexant was 5.2 area %.
Purification of Suvorexant by Extraction and
Crystallization-Procedure:
To a solution of Suvorexant (32.6 g) in MeOH (326 mL),
CH.sub.2Cl.sub.2 (163 mL), and H.sub.2O (114 mL) at 45.degree. C.
was added NaHCO.sub.3 in order to adjust the pH-value to pH=10.0
and the solution was stirred at 45.degree. C. for two hours.
CH.sub.2Cl.sub.2 (640 mL) and H.sub.2O (320 mL) was added, the
organic layer was separated, and concentrated to a total volume of
approximately 120 mL. Acetonitril (720 mL) was added and the
solution was concentrated to a total weight of approximately 160 g.
H.sub.2O (360 mL) was added at room temperature. The solid was
filtered, washed with H.sub.2O and dried at 45.degree. C. over
night to give Suvorexant (29.3 g, 90%) with an assay of 96.7 area %
according to HPLC. The assay of the "regioisomer" of Suvorexant was
0.9 area %.
* * * * *